Remote sensing of HIV care programmes using centrally collected laboratory results: Can we monitor ART programme effectiveness?

Aims. We describe a monitoring system at population level of patients on antiretroviral therapy (ART) using centrally collected laboratory data. We demonstrate an analogous process of remote sensing using a large set of laboratory results and illustrate the tremendous density of information stored. We moved from an individual to a community view of ART rollout, similar to remote sensing used in the earth and biological sciences when the spatial scale of the investigation is too large to be performed at ground level. Methods. This was a retrospective cohort study of patients from January 2004 to June 2011. A total of 188 759 individual laboratory results representing 26 445 patients were analysed for average CD4 and viral load by year. Results. The data showed an increasing state of health of the population and allowed for hypothesis generation when the trends did not follow expected paths. Conclusion. In this analysis we moved away from individual-centred data to population-level data in order to assess ART programme performance. Routine patient-monitoring data had great utility in assessment of population health. These methods are useful in monitoring and evaluation and effectiveness studies as they are easy to collect, reliable (not requiring much human matching or interventions) and scalable from a single clinic to an entire population. The larger the sample size, the more reliable the results, as confounders (such as incorrectly identified transfers out, lost-to-follow-up patients and transfers in) would be removed

Not All Are Lost: Interrupted Laboratory Monitoring, Early Death, and Loss to Follow-Up (LTFU) in a Large South African Treatment Program

Background: Many HIV treatment programs in resource-limited settings are plagued by high rates of loss to follow-up (LTFU). Most studies have not distinguished between those who briefly interrupt, but return to care, and those more chronically lost to follow-up. Methods: We conducted a retrospective cohort study of 11,397 adults initiating antiretroviral therapy (ART) in 71 Southern African Catholic Bishops Conference/Catholic Relief Services HIV treatment clinics between January 2004 and December 2008. We distinguished among patients with early death, within the first 7 months on ART; patients with interruptions in laboratory monitoring (ILM), defined as missing visits in the first 7 months on ART, but returning to care by 12 months; and those LTFU, defined as missing all follow-up visits in the first 12 months on ART. We used multilevel logistic regression models to determine patient and clinic-level characteristics associated with these outcomes. Results: In the first year on ART, 60% of patients remained in care, 30% missed laboratory visits, and 10% suffered early death. Of the 3,194 patients who missed laboratory visits, 40% had ILM, resuming care by 12 months. After 12 months on ART, patients with ILM had a 30% increase in detectable viremia compared to those who remained in care. Risk of LTFU decreased with increasing enrollment year, and was lowest for patients who enrolled in 2008 compared to 2004 [OR 0.49, 95%CI 0.39–0.62]. Conclusions: In a large community-based cohort in South Africa, nearly 30% of patients miss follow-up visits for CD4 monitoring in the first year after starting ART. Of those, 40% have ILM but return to clinic with worse virologic outcomes than those who remain in care. The risk of chronic LTFU decreased with enrollment year. As ART availability increases, interruptions in care may become more common, and should be accounted for in addressing program LTFU

A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.</p

Altered plasma protein profiles in genetic FTD – a GENFI study

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Methods: Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins. Results: We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers. Conclusion: We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.Open access funding provided by Karolinska Institute. C.G. received funding from EU Joint Programme—Neurodegenerative Disease Research -Prefrontals Vetenskapsrådet Dnr 529–2014-7504, Vetenskapsrådet 2015–02926, Vetenskapsrådet 2018–02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation, Dementia Foundation and Region Stockholm ALF-project. PN received funding from KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, the Swedish FTD Inititative-Schörling Foundation and Åhlén foundation. D.G. received support from the EU Joint Programme—Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. E.F. has received funding from a Canadian Institute of Health Research grant #327387. F.M. received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease. J.B.R. has received funding from the Welcome Trust (103838) and is supported by the Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council (SUAG/051 G101400) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215–20014). J.C.V.S. was supported by the Dioraphte Foundation grant 09–02-03–00, Association for Frontotemporal Dementias Research Grant 2009, Netherlands Organization for Scientific Research grant HCMI 056–13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield Project. J.D.R. is supported by the Bluefield Project and the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and a Miriam Marks Brain Research UK Senior Fellowship. M.M. has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. M.O. has received funding from Germany’s Federal Ministry of Education and Research (BMBF). R.S-V. is supported by Alzheimer’s Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2) and has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). R.V. has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. This work was also supported by the EU Joint Programme—Neurodegenerative Disease Research GENFI-PROX grant [2019–02248; to J.D.R., M.O., B.B., C.G., J.C.V.S. and M.S.info:eu-repo/semantics/publishedVersio

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Knowledge about and attitudes towards infant feeding of mothers with HIV infection

M.Cu

Loss to follow-up in a community clinic in South Africa - roles of gender, pregnancy, and CD4 count

BACKGROUND: Faith-based organizations have expanded access to antiretroviral therapy (ART) in community clinics across South Africa. Loss to follow-up (LTFU), however, limits both the potential individual and population treatment benefits and is an obstacle to optimal care. OBJECTIVE: To identify patient characteristics associated with LTFU six months after starting ART in patients in a large South African community clinic. METHODS: Patients initiating ART between April 2004 and October 2006 in one Catholic Relief Services HIV treatment clinic who had at least one follow-up visit were included in the analysis. Standardized instruments were used for data collection. Routine monitoring was performed every 6 months following ART initiation. Rates of LTFU over time were estimated by the Kaplan-Meier method. The log-rank test was used to examine the impact of age, baseline CD4 count, HIV RNA, gender and pregnancy status for women on LTFU. Cox proportional hazard regression was performed to analyze hazard ratios for LTFU. RESULTS: Data from 925 patients (age > 14 years), median age 36 years, 70% female (16% pregnant) were included in the analysis. Fifty one patients (6%) were lost to follow-up six months after ART initiation. When stratified by baseline CD4 count, gender and pregnancy status, pregnant women with lower baseline CD4 count (≤200 /μl) had 6.06 times (95% CI: 2.20 – 16.71) the hazard of LTFU compared to men. CONCLUSIONS: HIV-infected pregnant women initiating ART are significantly more likely to be lost to follow-up in a community clinic in South Africa. Interventions to successfully retain pregnant women in care are urgently needed

Loss to follow-up in a community clinic in South Africa – roles of gender, pregnancy and CD4 count

BACKGROUND: Faith-based organisations have expanded antiretroviral therapy (ART) in community clinics across South Africa. Loss to follow-up (LTFU), however, limits the potential individual and population treatment benefits and optimal care. OBJECTIVE: To identify patient characteristics associated with LTFU 6 months after starting ART in a large community clinic. METHODS: Patients initiating ART between April 2004 and October 2006 in one South African Catholic Bishops’ Conference HIV treatment clinic who had at least one follow-up visit were included and routinely monitored every 6 months after ART initiation. Standardised instruments were used to collect data. Rates of LTFU over time were estimated by the Kaplan-Meier method. The Cox proportional hazard regression examined the impact of age, baseline CD4 count, baseline HIV RNA, gender and pregnancy status on LTFU. RESULTS: Data from 925 patients (age >14 years, median age 36 years, 70% female, of whom 16% were pregnant) were included: 51 (6%) were lost to follow-up 6 months after ART initiation. Younger age (≤30 years) (hazard ratio (HR) 2.14, 95% confidence interval (CI) 1.05 - 4.38) and pregnancy for women (HR 3.75, 95% CI 1.53 - 9.16) were significantly associated with higher LTFU rates. When stratified by baseline CD4 count, gender and pregnancy status, pregnant women with lower baseline CD4 counts (≤200 cells/μl) had 6.06 times the hazard (95% CI 2.20 - 16.71) of LTFU at 6 months compared with men. CONCLUSIONS: HIV-infected pregnant women initiating ART were significantly more likely to be lost to follow-up in a community clinic in South Africa. Urgent interventions to successfully retain pregnant women in care are needed

Summary of baseline patient and clinic characteristics in a cohort study of LTFU in a large South African ART program.

<p>LTFU: Loss to Follow Up, ART: Antiretroviral Therapy, IQR; Interquartile Range.</p