No evidence of neuronal damage as measured by neurofilament light chain in a HIV cure study utilising a kick-and-kill approach.

OBJECTIVE: HIV-remission strategies including kick-and-kill could induce viral transcription and immune-activation in the central nervous system, potentially causing neuronal injury. We investigated the impact of kick-and-kill on plasma neurofilament light (NfL), a marker of neuro-axonal injury, in RIVER trial participants commencing antiretroviral treatment (ART) during primary infection and randomly allocated to ART-alone or kick-and-kill (ART + vaccination + vorinostat (ART + V + V)). DESIGN: Sub-study measuring serial plasma NfL concentrations. METHODS: Plasma NfL (using Simoa digital immunoassay), plasma HIV-1 RNA (using single-copy assay) and total HIV-1 DNA (using quantitative polymerase chain reaction in peripheral CD4+ T-cells) were measured at randomisation (following ≥22 weeks ART), week 12 (on final intervention day in ART + V + V) and week 18 post-randomisation. HIV-specific T-cells were quantified by intracellular cytokine staining at randomisation and week 12. Differences in plasma NfL longitudinally and by study arm were analysed using mixed models and Student's t-test. Associations with plasma NfL were assessed using linear regression and rank statistics. RESULTS: At randomisation, 58 male participants had median age 32 years and CD4+ count 696 cells/µL. No significant difference in plasma NfL was seen longitudinally and by study arm, with median plasma NfL (pg/mL) in ART-only vs ART + V + V: 7.4 vs 6.4, p = 0.16 (randomisation), 8.0 vs 6.9, p = 0.22 (week 12) and 7.1 vs 6.8, p = 0.74 (week 18). Plasma NfL did not significantly correlate with plasma HIV-1 RNA and total HIV-1 DNA concentration in peripheral CD4+ T-cells at any timepoint. While higher HIV-specific T-cell responses were seen at week 12 in ART + V + V, there were no significant correlations with plasma NfL. In multivariate analysis, higher plasma NfL was associated with older age, higher CD8+ count and lower body mass index. CONCLUSIONS: Despite evidence of vaccine-induced HIV-specific T-cell responses, we observed no evidence of increased neuro-axonal injury using plasma NfL as a biomarker up to 18 weeks following kick-and-kill, compared with ART-only.

Causes of hospitalisation among a cohort of people with HIV from a London centre followed from 2011 to 2018.

BACKGROUND: We describe the spectrum of ICD-10 classified causes for hospitalisations occurring between 2011 and 2018 in a cohort of people living with HIV (PLHIV). METHODS: This sub-study includes 798 PLHIV participating in the Antiretroviral, Sexual Transmission Risk and Attitudes (ASTRA) questionnaire study who were recruited from a large London centre. A medical record review identified the occurrence and causes of hospitalisation from the date of questionnaire completion (February-December 2011) until 1 June 2018. Up to five causes were classified by an HIV clinician using the ICD-10 system. RESULTS: There were 274 hospitalisations in 153 people (rate = 5.8/100 person-years; 95% CI: 5.1, 6.5). Causes were wide-ranging; the most common were circulatory (16.8%), digestive (13.1%), respiratory (11.7%), infectious diseases (11.0%), injury/poisoning (10.6%), genitourinary diseases (9.9%) and neoplasms (9.1%). A tenth (27/274) of hospitalisations were related to at least one AIDS-defining illness. Median duration of hospitalisation was 5 days (IQR 2-9). At the time of hospitalisation, median CD4 count was high (510 cells/µl; IQR: 315-739), while median CD4 nadir was relatively low (113 cells/µl; IQR: 40-239). At admission, half of individuals (51%) had a previous AIDS-defining illness and 21% had viral load > 50 copies/ml. Individuals admitted for infectious diseases were particularly likely to have unfavourable HIV-related clinical characteristics (low CD4, viral non-suppression, not on antiretroviral therapy (ART), previous AIDS). CONCLUSIONS: In the modern combination antiretroviral therapy era, the spectrum of causes of hospitalisation in PLHIV in the UK is wide-ranging, highlighting the importance of holistic care for PLHIV, including prevention, early detection and treatment of comorbidities.

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.

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.

ADP-ribose and analogues bound to the deMARylating macrodomain from the bat coronavirus HKU4.

Macrodomains are proteins that recognize and hydrolyze ADP ribose (ADPR) modifications of intracellular proteins. Macrodomains are implicated in viral genome replication and interference with host cell immune responses. They are important to the infectious cycle of Coronaviridae and Togaviridae viruses. We describe crystal structures of the conserved macrodomain from the bat coronavirus (CoV) HKU4 in complex with ligands. The structures reveal a binding cavity that accommodates ADPR and analogs via local structural changes within the pocket. Using a radioactive assay, we present evidence of mono-ADPR (MAR) hydrolase activity. In silico analysis presents further evidence on recognition of the ADPR modification for hydrolysis. Mutational analysis of residues within the binding pocket resulted in diminished enzymatic activity and binding affinity. We conclude that the common structural features observed in the macrodomain in a bat CoV contribute to a conserved function that can be extended to other known macrodomains.

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

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.

The predictors of pain extent in people living with HIV.

OBJECTIVE: To investigate the prevalence of widespread pain among people with HIV (PWH) and describe associations with antiretroviral therapy (ART) and markers of HIV disease stage. DESIGN: Cross-sectional analysis of cohort study in the United Kingdom and Ireland. METHODS: Pain information was collected during the baseline visit (conducted from 2013 to 2015) through a self-completed manikin identifying pain at 15 sites from five body regions. Pain was classified as widespread if reported at at least four regions and at least seven sites, or regional otherwise. Chi-squared tests, Kruskal-Wallis tests and ordinal logistic regression were used to consider associations between pain extent and sociodemographic and HIV-related factors. RESULTS: Among the 1207 participants (614 PWH ≥ 50 years, 330 PWH < 50 years, 263 HIV-negative controls ≥50 years), pain was most commonly reported at the upper (left: 28.9%, right: 28.0%) and lower (left: 25.7%; right: 24.5%) leg, upper (18.6%) and lower (29.7%) back and shoulders (left: 16.0%; right: 16.8%). Widespread pain was more commonly reported in PWH than in HIV-negative controls (PWH ≥ 50 years: 18.7%; PWH < 50 years: 12.7%; HIV-negative ≥50 years: 9.5%) with regional pain reported in 47.6, 44.8 and 49.8%, respectively (global P = 0.001). In multivariable analyses, pain extent was greater in those with lower educational attainment, those exposed to more ART drugs, and those with a higher current CD4 cell count but longer exposure to immunosuppression. CONCLUSION: Widespread pain is commonly reported in PWH and is associated with longer duration of exposure to HIV, immunosuppression and ART. Our findings call for greater awareness, and interventions to support the management, of pain in PWH.

Conformational Changes in Tyrosine 11 of Neurotensin Are Required to Activate the Neurotensin Receptor 1.

Cell-cell communication via endogenous peptides and their receptors is vital for controlling all aspects of human physiology and most peptides signal through G protein-coupled receptors (GPCRs). Disordered peptides bind GPCRs through complex modes for which there are few representative crystal structures. The disordered peptide neurotensin (NT) is a neuromodulator of classical neurotransmitters such as dopamine and glutamate, through activation of neurotensin receptor 1 (NTS1). While several experimental structures show how NT binds NTS1, details about the structural dynamics of NT during and after binding NTS1, or the role of peptide dynamics on receptor activation, remain obscure. Here saturation transfer difference (STD) NMR revealed that the binding mode of NT fragment NT10-13 is heterogeneous. Epitope maps of NT10-13 at NTS1 suggested that tyrosine 11 (Y11) samples other conformations to those observed in crystal structures of NT-bound NTS1. Molecular dynamics (MD) simulations confirmed that when NT is bound to NTS1, residue Y11 can exist in two χ1 rotameric states, gauche plus (g+) or gauche minus (g-). Since only the g+ Y11 state is observed in all the structures solved to date, we asked if the g- state is important for receptor activation. NT analogues with Y11 replaced with 7-OH-Tic were synthesized to restrain the dynamics of the side chain. P(OH-TIC)IL bound NTS1 with the same affinity as NT10-13 but did not activate NTS1, instead acted as an antagonist. This study highlights that flexibility of Y11 in NT may be required for NT activation of NTS1.

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

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.

Structure of the SARS-Unique Domain C From the Bat Coronavirus HKU4.

Coronaviruses (CoVs) that cause infections such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome phylogenetically originate from bat CoVs. The coronaviral nonstructural protein 3 (nsp3) has been implicated in viral replication, polyprotein cleavage, and host immune interference. We report the structure of the C domain from the SARS-Unique Domain of bat CoV HKU4. The protein has a frataxin fold, consisting of 5 antiparallel ß strands packed against 2 α helices. Bioinformatics analyses and nuclear magnetic resonance experiments were conducted to investigate the function of HKU4 C. The results showed that HKU4 C engages in protein-protein interactions with the nearby M domain of nsp3. The HKU4 C residues involved in protein-protein interactions are conserved in group 2c CoVs, indicating a conserved function.

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity.

The literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

Inside the black box: Modeling "Life Writing" for lifelong health and well being.

We articulate the lifespan theory of change by which an attachment-focused integrative reminiscence intervention, "Life Writing", is expected to interrupt the continuing problem of insecure attachment in adults and reverse associated reduced health and well-being outcomes. Based on preliminary studies and previous research, Life Writing is expected to foster earned-secure attachment in adults who work through subjective memories of unresolved attachment trauma. Roughly two decades of research on integrative reminiscence interventions like Life Writing show their consistent and wide-ranging positive impact. However, the bulk of this research demonstrates that such programs work, without also clarifying how they work, leaving unanswered questions as to how change occurs and how benefits might continue to accrue to participants through the lifespan. This represents what are known as "black box" effects. A program and evaluation planning tool, The Netway, was used to 1) identify hypothesized links between program inputs, activities, outputs, outcomes, and long-term impacts; 2) to clarify the underlying assumptions related to the program's success; and 3) to consider the appropriate contexts for the program. The logic model presented here articulates the hypothesized causal pathway from insecure to earned-secure attachment, in preparation for rigorous empirical tests of the program's lifespan theory of change.

Early virological response to HIV treatment: can we predict who is likely to experience subsequent treatment failure? Results from an observational cohort study, London, UK.

INTRODUCTION: For people living with HIV, the first antiretroviral treatment (ART) regimen offers the best chance for a good virological response. Early identification of those unlikely to respond to first-line ART could enable timely intervention and increase chances of a good initial treatment response. In this study we assess the extent to which the HIV RNA viral load (VL) at 1 and 3 months is predictive of first-line treatment outcome at 6 months. Methods All previously ART-naive individuals starting ART at two London centres since 2000 with baseline (-180 to 3 days) VL >500 c/mL had a VL measurement between 6 and 12 months after starting ART, and at least one at month 1 (4-60 days) or month 3 (61-120 days) were included. Lack of treatment response was defined as (i) VL >200 copies/mL at 6 months or (ii) VL >200 copies/mL at 6 months or simultaneous switch in drugs from at least two different drug classes before 6 months. The association with VL measurements at 1 and 3 months post-ART; change from pre-ART in these values; and CD4 count measurements at 1 and 3 months were assessed using logistic regression models. The relative fit of the models was compared using the Akaike information criterion (AIC). RESULTS: A total of 198 out of 3258 individuals (6%) experienced lack of treatment response at 6 months (definition i), increasing to 511 (16%) for definition (ii). Those with a 1-month (day 4-60 window) VL of <1000, 1000-9999, 10,000-99,999 and >100,000 copies/ml had a 4%, 8%, 23% and 24% chance, respectively, of subsequently experiencing treatment non-response at 6 months (definition (i)). When considering the 3-month (day 61-120 window) VL, the chances of subsequently experiencing treatment non-response were, respectively, 3%, 25%, 67% and 75%. Results were similar for definition (ii). CONCLUSIONS: Whilst 3-month VL provides good discrimination between low and high risk of treatment failure, 1-month VL does not. Presence of a VL >10,000 copies/ml after 3 months of ART is a cutoff above which individuals are at a sufficiently higher risk of non-response that they may be considered for intervention.

Computational and Experimental Studies of ADP-Ribosylation.

The macrodomains are a multifunctional protein family that function as receptors and enzymes acting on poly(ADP-ribose), ADP-ribosylated proteins, and other metabolites of nicotinamide adenine dinucleotide (NAD+). Several new functions for macrodomains, such as nucleic acid binding and protein-protein interaction, have recently been identified in this family. Here, we discuss methods for the identification of new macrodomains in viruses and the prediction of their function. This is followed by the expression and purification of these proteins following overexpression in bacterial cells and confirmation of folding and function using biophysical methods.

SARS-unique fold in the Rousettus bat coronavirus HKU9.

The coronavirus nonstructural protein 3 (nsp3) is a multifunctional protein that comprises multiple structural domains. This protein assists viral polyprotein cleavage, host immune interference, and may play other roles in genome replication or transcription. Here, we report the solution NMR structure of a protein from the "SARS-unique region" of the bat coronavirus HKU9. The protein contains a frataxin fold or double-wing motif, which is an α + ß fold that is associated with protein/protein interactions, DNA binding, and metal ion binding. High structural similarity to the human severe acute respiratory syndrome (SARS) coronavirus nsp3 is present. A possible functional site that is conserved among some betacoronaviruses has been identified using bioinformatics and biochemical analyses. This structure provides strong experimental support for the recent proposal advanced by us and others that the "SARS-unique" region is not unique to the human SARS virus, but is conserved among several different phylogenetic groups of coronaviruses and provides essential functions.

Durability of viral suppression with first-line antiretroviral therapy in patients with HIV in the UK: an observational cohort study.

BACKGROUND: The length of time that people with HIV on antiretroviral therapy (ART) with viral load suppression will be able to continue before developing viral rebound is unknown. We aimed to investigate the rate of first viral rebound in people that have achieved initial suppression with ART, to determine factors associated with viral rebound, and to use these estimates to predict long-term durability of viral suppression. METHODS: The UK Collaborative HIV Cohort (UK CHIC) Study is an ongoing multicentre cohort study that brings together in a standardised format data on people with HIV attending clinics around the UK. We included participants who started ART with three or more drugs and who had achieved viral suppression (≤50 copies per mL) by 9 months after the start of ART (baseline). Viral rebound was defined as the first single viral load of more than 200 copies per mL or treatment interruption (for ≥1 month). We investigated factors associated with viral rebound with Poisson regression. These results were used to calculate the rate of viral rebound according to several key factors, including age, calendar year at start of ART, and time since baseline. RESULTS: Of the 16 101 people included, 4519 had a first viral rebound over 58 038 person-years (7·8 per 100 person-years, 95% CI 7·6-8·0). Of the 4519 viral rebounds, 3105 (69%) were defined by measurement of a single viral load of more than 200 copies per mL, and 1414 (31%) by a documented treatment interruption. The rate of first viral rebound declined substantially over time until 7 years from baseline. The other factors associated with viral rebound were current age at follow-up and calendar year at ART initiation (p<0·0001) and HIV risk group (p<0·0001); higher pre-ART CD4 count (p=0·0008) and pre-ART viral load (p=0·0003) were associated with viral rebound in the multivariate analysis only. For 1322 (29%) of the 3105 people with observed viral rebound, the next viral load value after rebound was 50 copies per mL or less with no regimen change. For HIV-positive men who have sex with men, our estimates suggest that the probability of first viral rebound reaches a plateau of 1·4% per year after 45 years of age, and 1·0% when accounting for the fact that 29% of viral rebounds are temporary elevations. INTERPRETATION: A substantial proportion of people on ART will not have viral rebound over their lifetime, which has implications for people with HIV and the planning of future drug development. FUNDING: UK Medical Research Council.

Non-Disclosure of HIV Status and Associations with Psychological Factors, ART Non-Adherence, and Viral Load Non-Suppression Among People Living with HIV in the UK.

Disclosure of HIV status to family, friends, and a stable partner may be linked to improved health outcomes for people living with HIV. This study assessed whether non-disclosure is associated with psychological symptoms, non-adherence to antiretroviral therapy (ART), and viral load (VL) non-suppression. A total of 3258 HIV-diagnosed individuals in the UK completed the confidential ASTRA study questionnaire (2011-2012). Participants reported whether they told anyone they had HIV; to which confidant(s) (friends, family, work colleagues, stable partner) and to what extent (none, some, most/all). The prevalence and factors associated with non-disclosure were assessed. Associations between non-disclosure and the following factors were established using modified Poisson regression with adjustment for socio-demographic factors (gender, age group, ethnicity), HIV-related factors (time since HIV diagnosis, ART status), and clinic: low social support (score ≤ 12 on modified Duke-UNC FSSQ); depression and anxiety symptoms (≥10 on PHQ-9 and GAD-7 respectively); self-reported ART non-adherence in past 2 weeks/3 months; VL non-suppression (clinic-recorded VL > 50 copies/mL among those who started ART ≥ 6 months ago). Among 3233 participants with disclosure data, the prevalence of non-disclosure to anyone was 16.6 % (n/N = 61/367) among heterosexual men, 15.7 % (98/626) among women, and 5.0 % (113/2240) among MSM. MSM were more likely to disclose to some/all friends compared to family (85.8 vs. 59.9 %) while heterosexuals were less likely to disclose to friends than family (44.1 vs. 61.1 % for men, 57.5 vs. 67.1 % for women). Among 1,631 participants with a stable partner, non-disclosure to a stable partner was 4.9 % for MSM, 10.9 % for heterosexual men, and 13.0 % for women. In adjusted analyses, older age (≥60 years), non-white ethnicity, more recent HIV diagnosis, and not having a stable partner were significantly associated with overall non-disclosure for MSM and heterosexual individuals. The prevalence of low social support was 14.4 %, of depression and anxiety symptoms 27.1 and 22.0 %, respectively, of ART non-adherence 31.8 %, and of viral load non-suppression on ART 9.8 %. There was no evidence that non-disclosure overall (versus disclosure to anyone) was associated with low social support, depression or anxiety symptoms, ART non-adherence or VL non-suppression among MSM or heterosexual individuals. However, compared to MSM who disclosed to 'none' or 'some' friends and family, MSM who disclosed to 'most or all' of their friends and family were more likely to have symptoms of depression (adjusted PR = 1.4, 95 % CI 1.2-1.7), anxiety (1.3, 1.1-1.6), and to report ART non-adherence (1.3, 1.1-1.5). In this large multicentre study of people living with HIV in the UK, non-disclosure was overall low, but higher for heterosexual individuals compared to MSM. Non-disclosure was not associated with higher prevalence of adverse health measures.

Choice of first-line antiretroviral therapy regimen and treatment outcomes for HIV in a middle income compared to a high income country: a cohort study.

BACKGROUND: The range of combination antiretroviral therapy (cART) regimens available in many middle-income countries differs from those suggested in international HIV treatment guidelines. We compared first-line cART regimens, timing of initiation and treatment outcomes in a middle income setting (HIV Centre, Belgrade, Serbia - HCB) with a high-income country (Royal Free London Hospital, UK - RFH). METHODS: All antiretroviral-naïve HIV-positive individuals from HCB and RFH starting cART between 2003 and 2012 were included. 12-month viral load and CD4 count responses were compared, considering the first available measurement 12-24 months post-cART. The percentage that had made an antiretroviral switch for any reason, or for toxicity and the percentage that had died by 36 months (the latest time at which sufficient numbers remained under follow-up) were investigated using standard survival methods. RESULTS: 361/597 (61 %) of individuals initiating cART at HCB had a prior AIDS diagnosis, compared to 337/1763 (19 %) at RFH. Median pre-ART CD4 counts were 177 and 238 cells/mm(3) respectively (p < 0.0001). The most frequently prescribed antiretrovirals were zidovudine with lamivudine (149; 25 %) and efavirenz [329, 55 %] at HCB and emtricitabine with tenofovir (899; 51 %) and efavirenz [681, 39 %] at RFH. At HCB, a median of 2 CD4 count measurements in the first year of cART were taken, compared to 5 at RFH (p < 0.0001). Median (IQR) CD4 cell increase after 12 months was +211 (+86, +359) and +212 (+105, +318) respectively. 287 (48 %) individuals from HCB and 1452 (82 %) from RFH had an available viral load measurement, of which 271 (94 %) and 1280 (88 %) were <400 copies/mL (p < 0.0001). After 36 months, comparable percentages had made at least one antiretroviral switch (77 % HCB vs. 78 % RFH; p = 0.23). However, switches for toxicity/patient choice were more common at RFH. After 12 and 36 months of cART 3 % and 8 % of individuals died at HCB, versus 2 % and 4 % at RFH (p < 0.0001). CONCLUSION: In middle-income countries, cART is usually started at an advanced stage of HIV disease, resulting in higher mortality rates than in high income countries, supporting improved testing campaigns for early detection of HIV infection and early introduction of newer cART regimens.

Socioeconomic status and response to antiretroviral therapy in high-income countries: a literature review.

It has been shown that socioeconomic factors are associated with the prognosis of several chronic diseases; however, there is no recent systematic review of their effect on HIV treatment outcomes. We aimed to review the evidence regarding the existence of an association of socioeconomic status with virological and immunological response to antiretroviral therapy (ART). We systematically searched the current literature using the database PubMed. We identified and summarized original research studies in high-income countries that assessed the association between socioeconomic factors (education, employment, income/financial status, housing, health insurance, and neighbourhood-level socioeconomic factors) and virological response, immunological response, and ART nonadherence among people with HIV-prescribed ART. A total of 48 studies met the inclusion criteria (26 from the United States, six Canadian, 13 European, and one Australian), of which 14, six, and 35 analysed virological, immunological, and ART nonadherence outcomes, respectively. Ten (71%), four (67%), and 23 (66%) of these studies found a significant association between lower socioeconomic status and poorer response, and none found a significant association with improved response. Several studies showed that adjustment for nonadherence attenuated the association between socioeconomic status and ART response. Our review provides strong support that socioeconomic disadvantage is associated with poorer response to ART. However, most studies have been conducted in settings such as the United States without universal free healthcare access. Further study in settings with free access to ART could help assess the impact of socioeconomic status on ART outcomes and the mechanisms by which it operates.

HIV co-receptor tropism prediction remains stable over time in treatment-naïve patients.

HIV co-receptor tropism determination is essential before prescribing the CCR5 antagonist maraviroc. British HIV Association guidelines suggest tropism testing may remain valid for only 90 days in antiretroviral-naïve patients. We aimed to determine the accuracy of this figure. Tropism was assessed in 26 antiretroviral-naïve patients with ongoing viral replication, sampled yearly from first clinic visit. The V3 region of HIV-1 was sequenced in triplicate, then tropism predicted using the Geno2Pheno system. Baseline tropism prediction remained valid for a median of 52 months (range 7-81). For 19/26 individuals baseline tropism remained unchanged throughout a median of 54 months follow-up; 18 R5 tropic and 1 X4 tropic. In seven patients (27%) baseline tropism switched at least once (range 1-4 switches) during follow-up; however, their baseline tropism prediction remained valid for a median of 45 months. Co-receptor tropism in treatment-naïve patients with ongoing viral replication appears highly stable over time, suggesting that baseline genotypic tropism prediction may be valid for a longer duration in patients delaying ART initiation. In this study, baseline tropism prediction remained valid for a median of 52 months, suggesting current guidelines recommending repeat testing after 90 days may be excessively conservative in their assessment of tropism stability.