Publications by authors named "Colette Smith"

139 Publications

Hemodiafiltration maintains a sustained improvement in blood pressure compared to conventional hemodialysis in children-the HDF, heart and height (3H) study.

Pediatr Nephrol 2021 Feb 24. Epub 2021 Feb 24.

University College London Great Ormond Street Hospital for Children and Institute of Child Health, London, UK.

Background: Hypertension is prevalent in children on dialysis and associated with cardiovascular disease. We studied the blood pressure (BP) trends and the evolution of BP over 1 year in children on conventional hemodialysis (HD) vs. hemodiafiltration (HDF).

Methods: This is a post hoc analysis of the "3H - HDF-Hearts-Height" dataset, a multicenter, parallel-arm observational study. Seventy-eight children on HD and 55 on HDF who had three 24-h ambulatory BP monitoring (ABPM) measures over 1 year were included. Mean arterial pressure (MAP) was calculated and hypertension defined as 24-h MAP standard deviation score (SDS) ≥95th percentile.

Results: Poor agreement between pre-dialysis systolic BP-SDS and 24-h MAP was found (mean difference - 0.6; 95% limits of agreement -4.9-3.8). At baseline, 82% on HD and 44% on HDF were hypertensive, with uncontrolled hypertension in 88% vs. 25% respectively; p < 0.001. At 12 months, children on HDF had consistently lower MAP-SDS compared to those on HD (p < 0.001). Over 1-year follow-up, the HD group had mean MAP-SDS increase of +0.98 (95%CI 0.77-1.20; p < 0.0001), whereas the HDF group had a non-significant increase of +0.15 (95%CI -0.10-0.40; p = 0.23). Significant predictors of MAP-SDS were dialysis modality (β = +0.83 [95%CI +0.51 - +1.15] HD vs. HDF, p < 0.0001) and higher inter-dialytic-weight-gain (IDWG)% (β = 0.13 [95%CI 0.06-0.19]; p = 0.0003).

Conclusions: Children on HD had a significant and sustained increase in BP over 1 year compared to a stable BP in those on HDF, despite an equivalent dialysis dose. Higher IDWG% was associated with higher 24-h MAP-SDS in both groups.
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http://dx.doi.org/10.1007/s00467-021-04930-2DOI Listing
February 2021

Prospective association of social circumstance, socioeconomic, lifestyle and mental health factors with subsequent hospitalisation over 6-7 year follow up in people living with HIV.

EClinicalMedicine 2021 Jan 1;31:100665. Epub 2020 Dec 1.

Institute for Global Health, UCL, London, United Kingdom.

Background: Predictors of hospitalisation in people with HIV (PLHIV) in the contemporary treatment era are not well understood.

Methods: This ASTRA sub-study used clinic data linkage and record review to determine occurrence of hospitalisations among 798 PLHIV from baseline questionnaire (February to December 2011) until 1 June 2018. Associations of baseline social circumstance, socioeconomic, lifestyle, mental health, demographic and clinical factors with repeated all-cause hospitalisation from longitudinal data were investigated using Prentice-Williams-Peterson models. Associations were also assessed in 461 individuals on antiretroviral therapy (ART) with viral load ≤50 copies/ml and CD4 count ≥500 cells/ µl.

Findings: Rate of hospitalisation was 5.8/100 person-years (95% CI: 5.1-6.5). Adjusted for age, demographic group and time with diagnosed HIV, the following social circumstance, socioeconomic, lifestyle and mental health factors predicted hospitalisation: no stable partner (adjusted hazard ratio (aHR)=1.59; 95% CI=1.16-2.20 vs living with partner); having children (aHR=1.50; 1.08-2.10); non-employment (aHR=1.56; 1.07-2.27 for unemployment; aHR=2.39; 1.70-3.37 for sick/disabled vs employed); rented housing (aHR=1.72; 1.26-2.37 vs homeowner); not enough money for basic needs (aHR=1.82; 1.19-2.78 vs enough); current smoking (aHR=1.39; 1.02-1.91 vs never); recent injection-drug use (aHR=2.11; 1.30-3.43); anxiety symptoms (aHRs=1.39; 1.01-1.91, 2.06; 1.43-2.95 for mild and moderate vs none/minimal); depressive symptoms (aHRs=1.67; 1.17-2.38, 1.91; 1.30-2.78 for moderate and severe vs none/minimal); treated/untreated depression (aHRs=1.65; 1.03-2.64 for treated depression only, 1.87; 1.39-2.52 for depressive symptoms only; 1.53; 1.05-2.24; for treated depression and depressive symptoms, versus neither). Associations were broadly similar in those with controlled HIV and high CD4.

Interpretation: Social circumstance, socioeconomic disadvantage, adverse lifestyle factors and poorer mental health are strong predictors of hospitalisation in PLHIV, highlighting the need for targeted interventions and care.

Funding: British HIV Association (BHIVA) Research Award (2017); SMR funded by a PhD fellowship from the Royal Free Charity.
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http://dx.doi.org/10.1016/j.eclinm.2020.100665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846674PMC
January 2021

Understanding Mental Health in the Context of Adolescent Pregnancy and HIV in Sub-Saharan Africa: A Systematic Review Identifying a Critical Evidence Gap.

AIDS Behav 2021 Jan 15. Epub 2021 Jan 15.

Institute for Global Health, University College London, London, UK.

Adolescent (10-19 years) mental health remains an overlooked global health issue. Rates of adolescent pregnancy within sub-Saharan Africa are some of the highest in the world and occur at the epicentre of the global HIV epidemic. Both experiencing adolescent pregnancy and living with HIV have been found to be associated with adverse mental health outcomes, when investigated separately. Poor mental health may have implications for both parent and child. The literature regarding mental health within groups experiencing both HIV and adolescent pregnancy is yet to be summarised. This systematic review sought to identify (1) the prevalence/occurrence of common mental disorder amongst adolescents who are living with HIV and have experienced pregnancy, (inclusive of adolescent fathers) in sub-Saharan Africa (2) risk and protective factors for common mental disorder among this group, and (3) interventions (prevention/treatment) for common mental disorder among this group. A systematic search of electronic databases using pre-defined search terms, supplemented by hand-searching, was undertaken in September 2020. One author and an independent researcher completed a title and abstract screening of results from the search. A full-text search of all seemingly relevant manuscripts (both quantitative and qualitative) was undertaken and data extracted using pre-determined criteria. A narrative synthesis of included studies is provided. Quality and risk of bias within included studies was assessed using the Newcastle-Ottawa scale. A systematic keyword search of databases and follow-up hand searching identified 2287 unique records. Of these, thirty-eight full-text quantitative records and seven full-text qualitative records were assessed for eligibility. No qualitative records met the eligibility criteria for inclusion within the review. One quantitative record was identified for inclusion. This study reported on depressive symptomology amongst 14 pregnant adolescents living with HIV in Kenya, identifying a prevalence of 92.9%. This included study did not meet the high methodological quality of this review. No studies were identified reporting on risk and protective factors for common mental disorder, and no studies were found identifying any specific interventions for common mental disorder for this group, either for prevention or for treatment. The limited data identified within this review provides no good quality evidence relating to the prevalence of common mental disorder among adolescents living with HIV who have experienced pregnancy in sub-Saharan Africa. No data was available relating to risk and protective factors or interventions for psychological distress amongst this group. This systematic review identifies a need for rigorous evidence regarding the mental health of pregnant and parenting adolescents living with HIV, and calls for granular interrogation of existing data to further our understanding of the needs of this group. The absence of research on this topic (both quantitative and qualitative) is a critical evidence gap, limiting evidence-based policy and programming responses, as well as regional development opportunities.
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http://dx.doi.org/10.1007/s10461-020-03138-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810185PMC
January 2021

Improved treatment completion for tuberculosis patients: The case for a dedicated social care team.

J Infect 2020 Dec 24. Epub 2020 Dec 24.

UCL Respiratory, University College London, London United Kingdom; Department of Respiratory Medicine, Royal Free London NHS Foundation Trust, London United Kingdom. Electronic address:

Objectives: The increasing social needs of people with Tuberculosis (TB), and the poor adherence to anti-TB therapy (ATT) associated with homelessness, drug or alcohol abuse, and prison history, led us to introduce a social care team (SCT) to support patient engagement with care within this low TB incidence setting.

Methods: Using a risk assessment, patients with social risk factors (SRF) for non-adherence to ATT are identified and a referral made to the SCT, who then provide intensive casework support for areas including homelessness, housing, benefits, debt and immigration. Retrospective data analysis of the social care database from 2017 to 2019 was conducted. Patients who were (n = 170) and were not referred to the SCT (n = 734) were compared.

Results: Patients referred were significantly more likely to complete treatment for TB than those not (88.2% versus 77.7% respectively, p = 0.0025), irrespective of receipt of Directly/Video Observed Therapy and adjusting for confounders.

Conclusions: This paper demonstrates important evidence for the positive impact of a dedicated SCT within a TB service, and these improved treatment outcomes provide a strong argument for development of similar SCTs within UK TB services and similar healthcare settings.
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http://dx.doi.org/10.1016/j.jinf.2020.12.019DOI Listing
December 2020

Clinical outcomes of two-drug regimens vs. three-drug regimens in antiretroviral treatment-experienced people living with HIV.

Clin Infect Dis 2020 Dec 23. Epub 2020 Dec 23.

Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, University College London, London, UK.

Background: Limited data exist comparing clinical outcomes of two-drug regimens (2DRs) and three-drug regimens (3DRs) in people living with HIV.

Methods: Antiretroviral treatment-experienced individuals in RESPOND switching to a new 2DR or 3DR from 1/1/12-1/10/18 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression.

Results: Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median 52.6 years [interquartile range 46.7-59.0] vs 47.7 [39.7-54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%).There were 619 events during 27,159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU [95% CI 20.7-24.5]) on 3DRs, 79 (30.9/1000 PYFU [24.8-38.5]) on 2DRs. The most common events were death (7.5/1000 PYFU [95% CI 6.5-8.6]) and non-AIDS cancer (5.8/1000 PYFU [4.9-6.8]). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio: 0.92 [0.72-1.19]; p=0.53).

Conclusions: This is the first large, international cohort assessing clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes; further research on resistance barriers and long-term durability of 2DRs is needed.
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http://dx.doi.org/10.1093/cid/ciaa1878DOI Listing
December 2020

The impact of HIV infection on tuberculosis transmission in a country with low tuberculosis incidence: a national retrospective study using molecular epidemiology.

BMC Med 2020 12 14;18(1):385. Epub 2020 Dec 14.

Institute for Global Health, University College London, London, UK.

Background: HIV is known to increase the likelihood of reactivation of latent tuberculosis to active TB disease; however, its impact on tuberculosis infectiousness and consequent transmission is unclear, particularly in low-incidence settings.

Methods: National surveillance data from England, Wales and Northern Ireland on tuberculosis cases in adults from 2010 to 2014, strain typed using 24-locus mycobacterial-interspersed-repetitive-units-variable-number-tandem-repeats was used retrospectively to identify clusters of tuberculosis cases, subdivided into 'first' and 'subsequent' cases. Firstly, we used zero-inflated Poisson regression models to examine the association between HIV status and the number of subsequent clustered cases (a surrogate for tuberculosis infectiousness) in a strain type cluster. Secondly, we used logistic regression to examine the association between HIV status and the likelihood of being a subsequent case in a cluster (a surrogate for recent acquisition of tuberculosis infection) compared to the first case or a non-clustered case (a surrogate for reactivation of latent infection).

Results: We included 18,864 strain-typed cases, 2238 were the first cases of clusters and 8471 were subsequent cases. Seven hundred and fifty-nine (4%) were HIV-positive. Outcome 1: HIV-positive pulmonary tuberculosis cases who were the first in a cluster had fewer subsequent cases associated with them (mean 0.6, multivariable incidence rate ratio [IRR] 0.75 [0.65-0.86]) than those HIV-negative (mean 1.1). Extra-pulmonary tuberculosis (EPTB) cases with HIV were less likely to be the first case in a cluster compared to HIV-negative EPTB cases. EPTB cases who were the first case had a higher mean number of subsequent cases (mean 2.5, IRR (3.62 [3.12-4.19]) than those HIV-negative (mean 0.6). Outcome 2: tuberculosis cases with HIV co-infection were less likely to be a subsequent case in a cluster (odds ratio 0.82 [0.69-0.98]), compared to being the first or a non-clustered case.

Conclusions: Outcome 1: pulmonary tuberculosis-HIV patients were less infectious than those without HIV. EPTB patients with HIV who were the first case in a cluster had a higher number of subsequent cases and thus may be markers of other undetected cases, discoverable by contact investigations. Outcome 2: tuberculosis in HIV-positive individuals was more likely due to reactivation than recent infection, compared to those who were HIV-negative.
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http://dx.doi.org/10.1186/s12916-020-01849-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734856PMC
December 2020

All-cause hospitalization according to demographic group in people living with HIV in the current antiretroviral therapy era.

AIDS 2021 02;35(2):245-255

Institute for Global Health, UCL.

Objective: We investigated differences in all-cause hospitalization between key demographic groups among people with HIV in the UK in the current antiretroviral therapy (ART) era.

Design/methods: We used data from the Royal Free HIV Cohort study between 2007 and 2018. Individuals were classified into five groups: MSM, Black African men who have sex with women (MSW), MSW of other ethnicity, Black African women and women of other ethnicity. We studied hospitalizations during the first year after HIV diagnosis (Analysis-A) separately from those more than one year after diagnosis (Analysis-B). In Analysis-A, time to first hospitalization was assessed using Cox regression adjusted for age and diagnosis date. In Analysis-B, subsequent hospitalization rate was assessed using Poisson regression, accounting for repeated hospitalization within individuals, adjusted for age, calendar year, time since diagnosis.

Results: The hospitalization rate was 30.7/100 person-years in the first year after diagnosis and 2.7/100 person-years subsequently; 52% and 13% hospitalizations, respectively, were AIDS-related. Compared with MSM, MSW and women were at much higher risk of hospitalization during the first year [aHR (95% confidence interval, 95% CI): 2.7 (1.7-4.3), 3.0 (2.0-4.4), 2.0 (1.3-2.9), 3.0 (2.0-4.5) for Black African MSW; other ethnicity MSW; Black African women; other ethnicity women respectively, Analysis-A] and remained at increased risk subsequently [corresponding aIRR (95% CI): 1.7 (1.2-2.4), 2.1 (1.5-2.8), 1.5 (1.1-1.9), 1.7 (1.2-2.3), Analysis-B].

Conclusion: In this setting with universal healthcare, substantial variation exists in hospitalization risk across demographic groups, both in early and subsequent periods after HIV diagnosis, highlighting the need for targeted interventions.
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http://dx.doi.org/10.1097/QAD.0000000000002750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810421PMC
February 2021

The Impact of Immunosuppression on Chronic Kidney Disease in People Living With Human Immunodeficiency Virus: The D:A:D Study.

J Infect Dis 2021 Feb;223(4):632-637

Centre for Clinical Research, Epidemiology, Modelling and Evaluation, Institute for Global Health, University College London, London, United Kingdom.

Background: Relations between different measures of human immunodeficiency virus-related immunosuppression and chronic kidney disease (CKD) remain unknown.

Methods: Immunosuppression measures included baseline, current, time-lagged and nadir CD4, years and percentage of follow-up (%FU) with CD4 ≤200 cells/μL, and CD4 recovery. CKD was defined as confirmed estimated glomerular filtration rate <60 mL/minute/1.73 m2.

Results: Of 33 791 persons, 2226 developed CKD. Univariably, all immunosuppression measures predicted CKD. Multivariably, the strongest predictor was %FU CD4 ≤200 cells/μL (0 vs >25%; incidence rate ratio [IRR], 0.77 [95% confidence interval [CI], .68-.88]), with highest effect in those at low D:A:D CKD risk (IRR, 0.45 [95% CI, .24-.80]) vs 0.80 [95% CI, .70-.93]).

Conclusions: Longer immunosuppression duration most strongly predicts CKD and affects persons at low CKD risk more.
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http://dx.doi.org/10.1093/infdis/jiaa396DOI Listing
February 2021

Cost effectiveness of testing HIV infected individuals for TB in a low TB/HIV setting.

J Infect 2020 08 27;81(2):289-296. Epub 2020 May 27.

Department of HIV and Respiratory Medicine, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, United Kingdom; UCL Respiratory, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom.

Objectives: Guidelines recommend routine testing for latent TB infection (LTBI) in people living with HIV. However there are few cost-effectiveness studies to justify this in contemporary high resource, low TB/HIV incidence settings. We sought to assess the uptake, yield and cost-effectiveness of testing for latent and active TB.

Methods: Adults attending an ambulatory HIV clinic in London, UK were prospectively recruited by stratified selection and tested for TB infection using symptom questionnaires, chest radiograph (CXR), tuberculin skin test (TST), T-Spot.TB and induced sputum. From this, 30 testing strategies were compared in a cost-effectiveness model including probabilistic sensitivity analysis using Monte Carlo simulation.

Results: 219 subjects were assessed; 95% were using antiretroviral therapy (ART). Smear negative, culture positive TB was present in 0.9% asymptomatic subjects, LTBI in 9%. Only strategies testing those from subSaharan Africa with a TST or interferon gamma release assay (IGRA) with or without CXR, or testing those from countries with a TB incidence of >40/100,000 with TST alone were cost-effective using a £30,000/QALY threshold.

Conclusions: Cost-effectiveness analysis in an adult HIV cohort with high ART usage suggests there is limited benefit beyond routine testing for latent TB in people from high and possibly medium TB incidence settings.
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http://dx.doi.org/10.1016/j.jinf.2020.05.055DOI Listing
August 2020

The effect of HIV status on the frequency and severity of acute respiratory illness.

PLoS One 2020 29;15(5):e0232977. Epub 2020 May 29.

Division of Medicine, UCL Respiratory, University College London, London, England, United Kingdom.

Introduction: Antiretroviral therapy has improved the health of people living with HIV (PLW-HIV), though less is known about how this impacts on acute respiratory illness. These illnesses are a common cause of ill health in the general population and any increase in their frequency or severity in PLW-HIV might have significant implications for health-related quality of life and the development of chronic respiratory disease.

Methods: In a prospective observational cohort study following PLW-HIV and HIV negative participants for 12 months with weekly documentation of any acute respiratory illness, we compared the frequency, severity and healthcare use associated with acute respiratory illnesses to determine whether PLW-HIV continue to have a greater frequency or severity of such illnesses despite antiretroviral therapy.

Results: We followed-up 136 HIV positive and 73 HIV negative participants for 12 months with weekly documentation of any new respiratory symptoms. We found that HIV status did not affect the frequency of acute respiratory illness: unadjusted incidence rates per person year of follow-up were 2.08 illnesses (95% CI 1.81-2.38) and 2.30 illnesses (1.94-2.70) in HIV positive and negative participants respectively, IRR 0.87 (0.70-1.07) p = 0.18. However, when acute respiratory illnesses occurred, PLW-HIV reported more severe symptoms (relative fold-change in symptom score 1.61 (1.28-2.02), p <0.001) and were more likely to seek healthcare advice (42% vs 18% of illnesses, odds ratio 3.32 (1.48-7.39), p = 0.003). After adjustment for differences in baseline characteristics, PLW-HIV still had higher symptom scores when unwell.

Conclusions: HIV suppression with antiretroviral therapy reduces the frequency of acute respiratory illness to background levels, however when these occur, they are associated with more severe self-reported symptoms and greater healthcare utilisation. Exploration of the reasons for this greater severity of acute respiratory illness may allow targeted interventions to improve the health of people living with HIV.

Trial Registration: ISRCTN registry (ISRCTN38386321).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232977PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259631PMC
August 2020

Decline in Hepatitis C Virus (HCV) Incidence in Men Who Have Sex With Men Living With Human Immunodeficiency Virus: Progress to HCV Microelimination in the United Kingdom?

Clin Infect Dis 2021 Jan;72(2):233-238

Royal Free Hospital NHS Trust, London, United Kingdom.

Background: Modeling of the London hepatitis C virus (HCV) epidemic in men who have sex with men (MSM) and are living with human immunodeficiency virus (HIV) suggested that early access to direct-acting antiviral (DAA) treatment may reduce incidence. With high rates of linkage to care, microelimination of HCV within MSM living with HIV may be realistic ahead of 2030 World Health Organization targets. We examined trends in HCV incidence in the pre- and post-DAA eras for MSM living with HIV in London and Brighton, United Kingdom.

Methods: A retrospective cohort study was conducted at 5 HIV clinics in London and Brighton between 2013 and 2018. Each site reported all acute HCV episodes during the study period. Treatment timing data were collected. Incidence rates and reinfection proportion were calculated.

Results: A total of.

378 acute HCV infections were identified, comprising 292 first infections and 86 reinfections. Incidence rates of acute HCV in MSM living with HIV peaked at 14.57/1000 person-years of follow-up (PYFU; 95% confidence interval [CI], 10.95-18.20) in 2015. Rates fell to 4.63/1000 PYFU (95% CI, 2.60 to 6.67) by 2018. Time from diagnosis to starting treatment declined from 29.8 (2013) to 3.7 months (2018).

Conclusions: We observed a 78% reduction in the incidence of first HCV episode and a 68% reduction in overall HCV incidence since the epidemic peak in 2015, which coincides with wider access to DAAs in England. Further interventions to reduce transmission, including earlier access to treatment and for reinfection, are likely needed for microelimination to be achieved in this population.
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http://dx.doi.org/10.1093/cid/ciaa021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840101PMC
January 2021

Determining virological suppression and resuppression by point-of-care viral load testing in a HIV care setting in sub-Saharan Africa.

EClinicalMedicine 2020 Jan 5;18:100231. Epub 2020 Jan 5.

Institute of Infection & Global Health, University of Liverpool, Liverpool, United Kingdom.

Background: This prospective pilot study explored same-day point-of-care viral load testing in a setting in Ghana that has yet to implement virological monitoring of antiretroviral therapy (ART).

Methods: Consecutive patients accessing outpatient care while on ART underwent HIV-1 RNA quantification by Xpert. Those with viraemia at the first measurement (T0) received immediate adherence counselling and were reassessed 8 weeks later (T1). Predictors of virological status were determined by logistic regression analysis. Drug resistance-associated mutations (RAMs) were detected by Sanger sequencing.

Findings: At T0, participants had received treatment for a median of 8·9 years; 297/333 (89·2%) were on NNRTI-based ART. The viral load was ≥40 copies/mL in 164/333 (49·2%) patients and ≥1000 copies/mL in 71/333 (21·3%). In the latter group, 50/65 (76·9%) and 55/65 (84·6%) harboured NRTI and NNRTI RAMs, respectively, and 27/65 (41·5%) had ≥1 tenofovir RAM. Among 150/164 (91·5%) viraemic patients that reattended at T1, 32/150 (21·3%) showed resuppression <40 copies/mL, comprising 1/65 (1·5%) subjects with T0 viral load ≥1000 copies/mL and 31/85 (36·5%) subjects with lower levels. A T0 viral load ≥1000 copies/mL and detection of RAMs predicted ongoing T1 viraemia independently of self-reported adherence levels. Among participants with T0 viral load ≥1000 copies/mL, 23/65 (35·4%) showed resuppression <1000 copies/mL; the response was more likely among those with higher adherence levels and no RAMs.

Interpretation: Same-day point-of-care viral load testing was feasible and revealed poor virological control and suboptimal resuppression rates despite adherence counselling. Controlled studies should determine optimal triaging modalities for same-day versus deferred viral load testing.

Funding: University of Liverpool, South Tees Infectious Diseases Research Fund.
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http://dx.doi.org/10.1016/j.eclinm.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948257PMC
January 2020

Tuberculosis following renal transplantation in England, Wales and Northern Ireland: a national registry-based cohort study.

Eur Respir J 2019 10 17;54(4). Epub 2019 Oct 17.

Institute for Global Health, University College London, London, UK.

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http://dx.doi.org/10.1183/13993003.02245-2018DOI Listing
October 2019

Engagement in care among youth living with parenterally-acquired HIV infection in Romania.

AIDS Care 2019 10 6;31(10):1290-1296. Epub 2019 May 6.

a HIV Department, "Dr.V.Babes" Clinical Hospital for Infectious and Tropical Diseases , Bucharest , Romania.

Transition from adolescent to adult care can be challenging for youth living with HIV. We conducted a cohort study of youth born between 1985 and 1993 and infected with HIV parenterally, followed by the same medical team from age 15 years or first clinic visit until age 25 years or 30 November 2016. A longitudinal continuum-of-care was constructed, categorizing individuals' status for each month of follow-up as: engaged in care (EIC); not in care (NIC: no clinic visits within past year); lost-to-follow-up (LTFU: NIC and did not return to clinic); or died. Five hundred and forty-five individuals (52% male) were followed for 4775 person-years. At age 15, 92% were EIC, decreasing to 84% at age 20 and 74% at age 25. Of those EIC, HIV outcomes improved with age: 79% and 52% had a CD4 ≥200 cells/µl and VL <400 cps/ml at age 15; increasing to 86% and 73% at age 20 and 87% and 80% at age 25. We conclude that youth infected during early childhood tended to disengage from care, even when followed by the same medical team for a lengthy period of time. For those that did engage in care, HIV-related outcomes improved from adolescence through adulthood.
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http://dx.doi.org/10.1080/09540121.2019.1612010DOI Listing
October 2019

Risk factors for antiretroviral therapy (ART) discontinuation in a large multinational trial of early ART initiators.

AIDS 2019 07;33(8):1385-1390

Institute for Global Health, UCL, London, UK.

Objective: We aimed to investigate potential causes of higher risk of treatment interruptions within the multicountry Strategic Timing of AntiRetroviral Treatment (START) trial in 2015.

Methods: We defined baseline as the date of starting antiretroviral therapy (ART) and a treatment interruption as discontinuing ART for at least 2 weeks. Participants were stratified by randomization arm and followed from baseline to earliest end date of the initial phase of START, death, date of consent withdrawn or date of first treatment interruption. Cox regression was used to calculate hazard ratios and 95% confidence intervals for factors that may predict treatment interruptions in each arm.

Results: Of the 3438 participants who started ART, 2286 were in the immediate arm and 1152 in the deferred arm. 12.9% of people in the immediate arm and 10.5% of people in the deferred arm experienced at least one treatment interruption by 3 years after starting ART. In adjusted analyses, age [hazard ratio for 35-50 years: 0.75 (95% confidence interval: 0.59-0.97) and >50 years: 0.53 (0.33-0.80) vs. <35 years], education status [hazard ratio for postgraduate education vs. less than high-school education (0.23 (0.10-0.50))] and region [hazard ratio for United States vs. Europe/Israel (3.16 (2.09-4.77))] were significantly associated with treatment interruptions in the immediate arm. In the deferred arm, age and education status were significantly associated with treatment interruptions.

Conclusion: Within START, we identified younger age and lower educational attainment as potential causes of ART interruption. There is a need to strengthen adherence advice and wider social support in younger people and those of lower education status.
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http://dx.doi.org/10.1097/QAD.0000000000002210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546512PMC
July 2019

Effects of Hemodiafiltration versus Conventional Hemodialysis in Children with ESKD: The HDF, Heart and Height Study.

J Am Soc Nephrol 2019 04 7;30(4):678-691. Epub 2019 Mar 7.

Nephrology Unit, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany.

Background: Hypertension and cardiovascular disease are common in children undergoing dialysis. Studies suggest that hemodiafiltration (HDF) may reduce cardiovascular mortality in adults, but data for children are scarce.

Methods: The HDF, Heart and Height study is a nonrandomized observational study comparing outcomes on conventional hemodialysis (HD) versus postdilution online HDF in children. Primary outcome measures were annualized changes in carotid intima-media thickness (cIMT) SD score and height SD score.

Results: We enrolled 190 children from 28 centers; 78 on HD and 55 on HDF completed 1-year follow-up. The groups were comparable for age, dialysis vintage, access type, dialysis frequency, blood flow, and residual renal function. At 1 year, cIMT SD score increased significantly in children on HD but remained static in the HDF cohort. On propensity score analysis, HD was associated with a +0.47 higher annualized cIMT SD score compared with HDF. Height SD score increased in HDF but remained static in HD. Mean arterial pressure SD score increased with HD only. Factors associated with higher cIMT and mean arterial pressure SD-scores were HD group, higher ultrafiltration rate, and higher 2-microglobulin. The HDF cohort had lower 2-microglobulin, parathyroid hormone, and high-sensitivity C-reactive protein at 1 year; fewer headaches, dizziness, or cramps; and shorter postdialysis recovery time.

Conclusions: HDF is associated with a lack of progression in vascular measures versus progression with HD, as well as an increase in height not seen in the HD cohort. Patient-related outcomes improved among children on HDF correlating with improved BP control and clearances. Confirmation through randomized trials is required.
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http://dx.doi.org/10.1681/ASN.2018100990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442347PMC
April 2019

Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis.

Rev Med Virol 2019 05 31;29(3):e2034. Epub 2019 Jan 31.

Department of Virology, Royal Free NHS Foundation Trust, London, UK.

Cytomegalovirus (CMV) infection does not usually produce symptoms when it causes primary infection, reinfection, or reactivation because these three types of infection are all controlled by the normal immune system. However, CMV becomes an important pathogen in individuals whose immune system is immature or compromised, such as the unborn child. Several vaccines against CMV are currently in clinical trials that aim to induce immunity in seronegative individuals and/or to boost the immunity of those with prior natural infection (seropositives). To facilitate estimation of the burden of disease and the need for vaccines that induce de novo immune responses or that boost pre-existing immunity to CMV, we conducted a systematic survey of the published literature to describe the global seroprevalence of CMV IgG antibodies. We estimated a global CMV seroprevalence of 83% (95%UI: 78-88) in the general population, 86% (95%UI: 83-89) in women of childbearing age, and 86% (95%UI: 82-89) in donors of blood or organs. For each of these three groups, the highest seroprevalence was seen in the World Health Organisation (WHO) Eastern Mediterranean region 90% (95%UI: 85-94) and the lowest in WHO European region 66% (95%UI: 56-74). These estimates of the worldwide CMV distribution will help develop national and regional burden of disease models and inform future vaccine development efforts.
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http://dx.doi.org/10.1002/rmv.2034DOI Listing
May 2019

Cytomegalovirus viral load parameters associated with earlier initiation of pre-emptive therapy after solid organ transplantation.

PLoS One 2019 25;14(1):e0210420. Epub 2019 Jan 25.

Centre for Virology University College London Medical School, London, United Kingdom.

Background: Human cytomegalovirus (HCMV) can be managed by monitoring HCMV DNA in the blood and giving valganciclovir when viral load exceeds a defined value. We hypothesised that such pre-emptive therapy should occur earlier than the standard 3000 genomes/ml (2520 IU/ml) when a seropositive donor transmitted virus to a seronegative recipient (D+R-) following solid organ transplantation (SOT).

Methods: Our local protocol was changed so that D+R- SOT patients commenced valganciclovir once the viral load exceeded 200 genomes/ml; 168 IU/ml (new protocol). The decision point remained at 3000 genomes/ml (old protocol) for the other two patient subgroups (D+R+, D-R+). Virological outcomes were assessed three years later, when 74 D+R- patients treated under the old protocol could be compared with 67 treated afterwards. The primary outcomes were changes in peak viral load, duration of viraemia and duration of treatment in the D+R- group. The secondary outcome was the proportion of D+R- patients who developed subsequent viraemia episodes.

Findings: In the D+R- patients, the median values of peak viral load (30,774 to 11,135 genomes/ml, p<0.0215) were significantly reduced on the new protocol compared to the old, but the duration of viraemia and duration of treatment were not. Early treatment increased subsequent episodes of viraemia from 33/58 (57%) to 36/49 (73%) of patients (p< 0.0743) with a significant increase (p = 0.0072) in those episodes that required treatment (16/58; 27% versus 26/49; 53%). Median peak viral load increased significantly (2,103 to 3,934 genomes/ml, p<0.0249) in the D+R+ but not in the D-R+ patient subgroups. There was no change in duration of viraemia or duration of treatment for any patient subgroup.

Interpretation: Pre-emptive therapy initiated at the first sign of viraemia post-transplant significantly reduced the peak viral load but increased later episodes of viraemia, consistent with the hypothesis of reduced antigenic stimulation of the immune system.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210420PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347177PMC
October 2019

Determinants of Restoration of CD4 and CD8 Cell Counts and Their Ratio in HIV-1-Positive Individuals With Sustained Virological Suppression on Antiretroviral Therapy.

J Acquir Immune Defic Syndr 2019 03;80(3):292-300

Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.

Background: An increasing number of HIV-positive individuals now start antiretroviral therapy (ART) with high CD4 cell counts. We investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics.

Methods: We determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2309 HIV-negative individuals. We used longitudinal measurements of 60,997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models.

Results: When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with <250 CD4 cells/mm. Median CD4:CD8 trajectories did not reach median reference values, even when ART was started at 500 cells/mm.

Discussion: Starting ART with a CD4 cell count of ≥500 cells/mm makes reaching median reference CD4 cell counts more likely. However, median CD4:CD8 ratio trajectories remained below the median levels of HIV-negative individuals because of persisting high CD8 cell counts. To what extent these subnormal immunological responses affect specific clinical endpoints requires further investigation.
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http://dx.doi.org/10.1097/QAI.0000000000001913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392208PMC
March 2019

Does Rheumatoid Arthritis Really Improve During Pregnancy? A Systematic Review and Metaanalysis.

J Rheumatol 2019 03 1;46(3):245-250. Epub 2018 Nov 1.

From the Rheumatology Department, London North West Healthcare National Health Service (NHS) Trust; General Medicine, Croydon University Hospital; Statistics Department, Royal Free Hospital; Centre for Rheumatology Research, Rayne Institute, University College London, London, UK.

Objective: We performed a systematic review and metaanalysis to assess rheumatoid arthritis (RA) disease activity during pregnancy using objective disease activity scoring systems.

Methods: A systematic review of PubMed, EMBASE/Medline, Cochrane, and LactMed databases was performed. Our inclusion criteria for analysis were prospective studies, more than 5 patients per study, and data on RA using an objective scoring system conducted by a clinician/health professional.

Results: Ten studies were eligible for final analysis, which included 237 patients, of which prepartum data were available for 204 patients. Postpartum disease activity was recorded in 135 pregnancies.

Conclusion: Disease activity improved in 60% of patients with RA in pregnancy and flared in 46.7% postpartum.
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http://dx.doi.org/10.3899/jrheum.180226DOI Listing
March 2019

Point-of-Care Screening for a Current Hepatitis C Virus Infection: Influence on Uptake of a Concomitant Offer of HIV Screening.

Sci Rep 2018 10 17;8(1):15297. Epub 2018 Oct 17.

Royal Liverpool University Hospital, Liverpool, United Kingdom.

Eliminating hepatitis C as a public health threat requires an improved understanding of how to increase testing uptake. We piloted point-of-care testing (POCT) for a current HCV infection in an inner-city Emergency Department (ED) and assessed the influence on uptake of offering concomitant screening for HIV. Over four months, all adults attending ED with minor injuries were first invited to complete an anonymous questionnaire then invited to test in alternating cycles offering HCV POCT or HCV+HIV POCT. Viral RNA was detected in finger-prick blood by GeneXpert. 814/859 (94.8%) questionnaires were returned and 324/814 (39.8%) tests were accepted, comprising 211 HCV tests and 113 HCV+HIV tests. Offering concomitant HIV screening reduced uptake after adjusting for age and previous HCV testing (odds ratio 0.51; 95% confidence interval [CI] 0.38-0.68; p < 0.001). HCV prevalence was 1/324 (0.31%; 95% CI 0.05-1.73); no participant tested positive for HIV. 167/297 (56.2%) POCT participants lived in the most deprived neighbourhoods in England. HCV RNA testing using finger-prick blood was technically feasible. Uptake was moderate and the offer of concomitant HIV screening showed a detrimental impact on acceptability in this low prevalence population. The findings should be confirmed in a variety of other community settings.
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http://dx.doi.org/10.1038/s41598-018-33172-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193009PMC
October 2018

Effect of haemodiafiltration vs conventional haemodialysis on growth and cardiovascular outcomes in children - the HDF, heart and height (3H) study.

BMC Nephrol 2018 08 10;19(1):199. Epub 2018 Aug 10.

Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany.

Background: Cardiovascular disease is prevalent in children on dialysis and accounts for almost 30% of all deaths. Randomised trials in adults suggest that haemodiafiltration (HDF) with high convection volumes is associated with reduced cardiovascular mortality compared to high-flux haemodialysis (HD); however paediatric data are scarce. We designed the haemodiafiltration, heart and height (3H) study to test the hypothesis that children on HDF have an improved cardiovascular risk profile, growth and nutritional status and quality of life, compared to those on conventional HD. We performed a non-randomised parallel-arm intervention study within the International Paediatric Haemodialysis Network Registry comparing children on HDF and conventional HD to determine annualised change in cardiovascular end-points and growth. Here we present the 3H study design and baseline characteristics of the study population.

Methods: 190 children were screened and 177 (106 on HD and 71 on HDF) recruited from 28 centres in 10 countries. There was no difference in age, underlying diagnosis, comorbidities, previous dialysis therapy, dialysis vintage, residual renal function, type of vascular access or blood flow between HD and HDF groups. High flux dialysers were used in 63% of HD patients and ultra-pure water was available in 52%. HDF patients achieved a median convection volume of 13.3 L/m; this was associated with the blood flow rate only ((p = 0.0004, r = 0.42) and independent of access type (p = 0.38).

Discussion: This is the largest study on dialysis outcomes in children that involves deep phenotyping across a wide range of cardiovascular, anthropometric, nutritional and health-related quality of life measures, to test the hypothesis that HDF leads to improved cardiovascular and growth outcomes compared to conventional HD.

Trial Registration: ClinicalTrials.gov: NCT02063776 . The trial was prospectively registered on the 14 Feb 2014.
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http://dx.doi.org/10.1186/s12882-018-0998-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086045PMC
August 2018

Drug resistance outcomes of long-term ART with tenofovir disoproxil fumarate in the absence of virological monitoring.

J Antimicrob Chemother 2018 11;73(11):3148-3157

Institute of Infection & Global Health, University of Liverpool, Liverpool, UK.

Objectives: The resistance profiles of patients receiving long-term ART in sub-Saharan Africa have been poorly described. This study obtained a sensitive assessment of the resistance patterns associated with long-term tenofovir-based ART in a programmatic setting where virological monitoring is yet to become part of routine care.

Methods: We studied subjects who, after a median of 4.2 years of ART, replaced zidovudine or stavudine with tenofovir disoproxil fumarate while continuing lamivudine and an NNRTI. Using deep sequencing, resistance-associated mutations (RAMs) were detected in stored samples collected at tenofovir introduction (T0) and after a median of 4.0 years (T1).

Results: At T0, 19/87 (21.8%) subjects showed a detectable viral load and 8/87 (9.2%) had one or more major NNRTI RAMs, whereas 82/87 (94.3%) retained full tenofovir susceptibility. At T1, 79/87 (90.8%) subjects remained on NNRTI-based ART, 5/87 (5.7%) had introduced lopinavir/ritonavir due to immunological failure, and 3/87 (3.4%) had interrupted ART. Whilst 68/87 (78.2%) subjects maintained or achieved virological suppression between T0 and T1, a detectable viral load with NNRTI RAMs at T0 predicted lack of virological suppression at T1. Each treatment interruption, usually reflecting unavailability of the dispensary, doubled the risk of T1 viraemia. Tenofovir, lamivudine and efavirenz selected for K65R, K70E/T, L74I/V and Y115F, alongside M184V and multiple NNRTI RAMs; this resistance profile was accompanied by high viral loads and low CD4 cell counts.

Conclusions: Viraemia on tenofovir, lamivudine and efavirenz led to complex resistance patterns with implications for continued drug activity and risk of onward transmission.
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http://dx.doi.org/10.1093/jac/dky281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198639PMC
November 2018

Trends in, and factors associated with, HIV infection amongst tuberculosis patients in the era of anti-retroviral therapy: a retrospective study in England, Wales and Northern Ireland.

BMC Med 2018 06 7;16(1):85. Epub 2018 Jun 7.

National Infections Service, Public Health England, 61 Colindale Avenue, London, NW9 5EQ, UK.

Background: HIV increases the progression of latent tuberculosis (TB) infection to active disease and contributed to increased TB in the UK until 2004. We describe temporal trends in HIV infection amongst patients with TB and identify factors associated with HIV infection.

Methods: We used national surveillance data of all TB cases reported in England, Wales and Northern Ireland from 2000 to 2014 and determined HIV status through record linkage to national HIV surveillance. We used logistic regression to identify associations between HIV and demographic, clinical and social factors.

Results: There were 106,829 cases of TB in adults (≥ 15 years) reported from 2000 to 2014. The number and proportion of TB patients infected with HIV decreased from 543/6782 (8.0%) in 2004 to 205/6461 (3.2%) in 2014. The proportion of patients diagnosed with HIV > 91 days prior to their TB diagnosis increased from 33.5% in 2000 to 60.2% in 2013. HIV infection was highest in people of black African ethnicity from countries with high HIV prevalence (32.3%), patients who misused drugs (8.1%) and patients with miliary or meningeal TB (17.2%).

Conclusions: There has been an overall decrease in TB-HIV co-infection and a decline in the proportion of patients diagnosed simultaneously with both infections. However, high rates of HIV remain in some sub-populations of patients with TB, particularly black Africans born in countries with high HIV prevalence and people with a history of drug misuse. Whilst the current policy of testing all patients diagnosed with TB for HIV infection is important in ensuring appropriate management of TB patients, many of these TB cases would be preventable if HIV could be diagnosed before TB develops. Improving screening for both latent TB and HIV and ensuring early treatment of HIV in these populations could help prevent these TB cases. British HIV Association guidelines on latent TB testing for people with HIV from sub-Saharan Africa remain relevant, and latent TB screening for people with HIV with a history of drug misuse, homelessness or imprisonment should also be considered.
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http://dx.doi.org/10.1186/s12916-018-1070-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992696PMC
June 2018

Long terms trends in CD4+ cell counts, CD8+ cell counts, and the CD4+ :  CD8+ ratio.

AIDS 2018 06;32(10):1361-1367

Population Health Sciences, Bristol Medical School.

Objective: Model trajectories of CD4+ and CD8+ cell counts after starting combination antiretroviral therapy (ART) and use the model to predict trends in these counts and the CD4+ : CD8+ ratio.

Design: Cohort study of antiretroviral-naïve HIV-positive adults who started ART after 1997 (ART Cohort Collaboration) with more than 6 months of follow-up data.

Methods: We jointly estimated CD4+ and CD8+ cell count trends and their correlation using a bivariate random effects model, with linear splines describing their population trends, and predicted the CD4+ : CD8+ ratio trend from this model. We assessed whether CD4+ and CD8+ cell count trends and the CD4+ : CD8+ ratio trend varied according to CD4+ cell count at start of ART (baseline), and, whether these trends differed in patients with and without virological failure more than 6 months after starting ART.

Results: A total of 39 979 patients were included (median follow-up was 53 months). Among patients with baseline CD4+ cell count at least 50 cells/μl, predicted mean CD8+ cell counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4+ : CD8+ ratio. During 15 years of follow-up, normalization of the predicted mean CD4+ : CD8+ ratio (to >1) was only observed among patients with baseline CD4+ cell count at least 200 cells/μl. A higher baseline CD4+ cell count predicted a shorter time to normalization.

Conclusion: Declines in CD8+ cell count and increases in CD4+ : CD8+ ratio occurred up to 15 years after starting ART. The likelihood of normalization of the CD4+ : CD8+ ratio is strongly related to baseline CD4+ cell count.
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http://dx.doi.org/10.1097/QAD.0000000000001848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991182PMC
June 2018

Direct bilirubin levels observed in prolonged neonatal jaundice: a retrospective cohort study.

BMJ Paediatr Open 2018 24;2(1):e000202. Epub 2018 Feb 24.

Clinical Biochemistry, Royal Free London NHS Foundation Trust, London, UK.

Objective: Prolonged neonatal jaundice is common and usually benign; however, assessment of bilirubin fractions is recommended to determine the need for further assessment for congenital liver disease, particularly biliary atresia. The direct (conjugated) bilirubin thresholds currently used are variable and poorly evidenced. Hence, we aimed to delineate direct bilirubin levels in disease-free neonates with prolonged jaundice.

Methods: We performed a retrospective cohort analysis of split bilirubin levels, and subsequent follow-up, for all neonates initially assessed in our prolonged neonatal jaundice clinic over 2 years. We plotted centile charts for total, direct and direct-total bilirubin ratio levels against age at sampling. The association was assessed using linear regression analysis.

Results: Data were collected for 420 neonates (501 blood samples) across an age range of 10-70 days. No significant liver disease was found. For each day of older age, total bilirubin fell by 3.72 µmol/L (95% CI 2.46 to 5.00) and direct bilirubin fell by 0.39 µmol/L (0.18 to 0.59). The ratio between the two did not change significantly (-0.0006 to +0.0034). The 95th centile for direct bilirubin was stable at ~25 µmol/L. Direct-total bilirubin ratio was very variable with some 95th centiles >30%.

Conclusions: In a clinically relevant population of disease-free neonates with prolonged jaundice both the total and the direct bilirubin decreased with age. The absolute direct bilirubin is more useful clinically than the direct-total bilirubin ratio. Our results support National Institute for Health and Care Excellence guidance that conjugated bilirubin >25 µmol/L, or even more stringent criteria, constitutes an appropriate threshold for further investigation for neonatal liver disease.
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http://dx.doi.org/10.1136/bmjpo-2017-000202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843007PMC
February 2018

Epitope-Specific Humoral Responses to Human Cytomegalovirus Glycoprotein-B Vaccine With MF59: Anti-AD2 Levels Correlate With Protection From Viremia.

J Infect Dis 2018 05;217(12):1907-1917

Institute for Immunity and Transplantation, University College London, United Kingdom.

The human cytomegalovirus (HCMV) virion envelope protein glycoprotein B (gB) is essential for viral entry and represents a major target for humoral responses following infection. Previously, a phase 2 placebo-controlled clinical trial conducted in solid organ transplant candidates demonstrated that vaccination with gB plus MF59 adjuvant significantly increased gB enzyme-linked immunosorbent assay (ELISA) antibody levels whose titer correlated directly with protection against posttransplant viremia. The aim of the current study was to investigate in more detail this protective humoral response in vaccinated seropositive transplant recipients. We focused on 4 key antigenic domains (AD) of gB (AD1, AD2, AD4, and AD5), measuring antibody levels in patient sera and correlating these with posttransplant HCMV viremia. Vaccination of seropositive patients significantly boosted preexisting antibody levels against the immunodominant region AD1 as well as against AD2, AD4, and AD5. A decreased incidence of viremia correlated with higher antibody levels against AD2 but not with antibody levels against the other 3 ADs. Overall, these data support the hypothesis that antibodies against AD2 are a major component of the immune protection of seropositives seen following vaccination with gB/MF59 vaccine and identify a correlate of protective immunity in allograft patients.
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http://dx.doi.org/10.1093/infdis/jiy102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972559PMC
May 2018

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

PLoS Med 2018 03 1;15(3):e1002514. Epub 2018 Mar 1.

Inserm (French Institute of Health and Medical Research), UMR 1027 Université Toulouse 3, Toulouse, France.

Background: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia.

Methods And Findings: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria.

Conclusion: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.
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http://dx.doi.org/10.1371/journal.pmed.1002514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832192PMC
March 2018

Increased non-AIDS mortality among persons with AIDS-defining events after antiretroviral therapy initiation.

J Int AIDS Soc 2018 01;21(1)

Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Introduction: HIV-1 infection leads to chronic inflammation and to an increased risk of non-AIDS mortality. Our objective was to determine whether AIDS-defining events (ADEs) were associated with increased overall and cause-specific non-AIDS related mortality after antiretroviral therapy (ART) initiation.

Methods: We included HIV treatment-naïve adults from the Antiretroviral Therapy Cohort Collaboration (ART-CC) who initiated ART from 1996 to 2014. Causes of death were assigned using the Coding Causes of Death in HIV (CoDe) protocol. The adjusted hazard ratio (aHR) for overall and cause-specific non-AIDS mortality among those with an ADE (all ADEs, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non-Hodgkin's lymphoma (NHL)) compared to those without an ADE was estimated using a marginal structural model.

Results: The adjusted hazard of overall non-AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). The adjusted hazard of each of the cause-specific non-AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths (malignancy aHR 2.59 (95% CI 2.13 to 3.14), accident/suicide/overdose aHR 1.37 (95% CI 1.05 to 1.79), cardiovascular aHR 1.95 (95% CI 1.54 to 2.48), infection aHR (95% CI 1.68 to 2.81), hepatic aHR 2.09 (95% CI 1.61 to 2.72), respiratory aHR 4.28 (95% CI 2.67 to 6.88), renal aHR 5.81 (95% CI 2.69 to 12.56) and central nervous aHR 1.53 (95% CI 1.18 to 5.44)). The risk of overall and cause-specific non-AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL).

Conclusions: In this large multi-centre cohort collaboration with standardized assignment of causes of death, non-AIDS mortality was twice as high among patients with an ADE compared to without an ADE. However, non-AIDS related mortality after an ADE depended on the ADE of interest. Although there may be unmeasured confounders, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. While prevention of ADEs may reduce subsequent death due to NADEs following ART initiation, modification of risk factors for NADE mortality remains important after ADE survival.
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http://dx.doi.org/10.1002/jia2.25031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810321PMC
January 2018

Resilience and Physical and Mental Well-Being in Adults with and Without HIV.

AIDS Behav 2018 05;22(5):1688-1698

Research Department of Infection and Population Health, University College London, London, UK.

Resilience has been related to improved physical and mental health, and is thought to improve with age. No studies have explored the relationship between resilience, ageing with HIV, and well-being. A cross sectional observational study performed on UK HIV positive (N = 195) and HIV negative adults (N = 130). Associations of both age and 'time diagnosed with HIV' with resilience (RS-14) were assessed, and the association of resilience with depression, anxiety symptoms (PHQ-9 and GAD-7), and problems with activities of daily living (ADLs) (Euroqol 5D-3L). In a multivariable model, HIV status overall was not related to resilience. However, longer time diagnosed with HIV was related to lower resilience, and older age showed a non-significant trend towards higher resilience. In adults with HIV, high resilience was related to a lower prevalence of depression, anxiety, and problems with ADLs. It may be necessary to consider resilience when exploring the well-being of adults ageing with HIV.
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http://dx.doi.org/10.1007/s10461-017-1980-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902512PMC
May 2018