Estimating the hospital costs of care for people living with HIV in England using routinely collected data.

BACKGROUND: Understanding the health care activity and associated hospital costs of caring for people living with HIV is an important component of assessing the cost effectiveness of new technologies and for budget planning. METHODS: Data collected between 2010 and 2017 from an English HIV treatment centre were combined with national reference costs to estimate the rate of hospital attendances and costs per quarter year, according to demographic and clinical factors. The final dataset included records for 1763 people living with HIV, which was analysed using negative binomial regression models and general estimating equations. RESULTS: People living with HIV experienced an unadjusted average of 0.028 (standard deviation [SD] 0.20) inpatient episodes per quarter, equivalent to one every 9 years, and 1.85 (SD 2.30) outpatient visits per quarter. The unadjusted mean quarterly cost per person with HIV (excluding antiretroviral drug costs) was £439 (SD 604). Outpatient appointments and inpatient episodes accounted for 88% and 6% of total costs, respectively. In adjusted models, low CD4 count was the strongest predictor of inpatient stays and outpatient visits. Low CD4 count and new patient status (having a first visit at the Trust in the last 6 months) were the factors that most increased estimated costs. Associations were weaker or less consistent for demographic factors (age, sex/sexual orientation/ethnicity). Sensitivity analyses suggest that the findings were generally robust to alternative parameter and modelling assumptions. CONCLUSION: A number of factors predicted hospital activity and costs, but CD4 cell count and new patient status were the strongest. The study results can be incorporated into future economic evaluations and budget impact assessments of HIV-related technologies.

Charge Radii of

Nuclear charge radii of ^{55,56}Ni were measured by collinear laser spectroscopy. The obtained information completes the behavior of the charge radii at the shell closure of the doubly magic nucleus ^{56}Ni. The trend of charge radii across the shell closures in calcium and nickel is surprisingly similar despite the fact that the ^{56}Ni core is supposed to be much softer than the ^{48}Ca core. The very low magnetic moment µ(^{55}Ni)=-1.108(20) µ_{N} indicates the impact of M1 excitations between spin-orbit partners across the N,Z=28 shell gaps. Our charge-radii results are compared to ab initio and nuclear density functional theory calculations, showing good agreement within theoretical uncertainties.

Constraining neutron-star matter with microscopic and macroscopic collisions.

Interpreting high-energy, astrophysical phenomena, such as supernova explosions or neutron-star collisions, requires a robust understanding of matter at supranuclear densities. However, our knowledge about dense matter explored in the cores of neutron stars remains limited. Fortunately, dense matter is not probed only in astrophysical observations, but also in terrestrial heavy-ion collision experiments. Here we use Bayesian inference to combine data from astrophysical multi-messenger observations of neutron stars1-9 and from heavy-ion collisions of gold nuclei at relativistic energies10,11 with microscopic nuclear theory calculations12-17 to improve our understanding of dense matter. We find that the inclusion of heavy-ion collision data indicates an increase in the pressure in dense matter relative to previous analyses, shifting neutron-star radii towards larger values, consistent with recent observations by the Neutron Star Interior Composition Explorer mission5-8,18. Our findings show that constraints from heavy-ion collision experiments show a remarkable consistency with multi-messenger observations and provide complementary information on nuclear matter at intermediate densities. This work combines nuclear theory, nuclear experiment and astrophysical observations, and shows how joint analyses can shed light on the properties of neutron-rich supranuclear matter over the density range probed in neutron stars.

Astrophysical Constraints on the Symmetry Energy and the Neutron Skin of

The symmetry energy and its density dependence are crucial inputs for many nuclear physics and astrophysics applications, as they determine properties ranging from the neutron-skin thickness of nuclei to the crust thickness and the radius of neutron stars. Recently, PREX-II reported a value of 0.283±0.071 fm for the neutron-skin thickness of ^{208}Pb, implying a slope parameter L=106±37 MeV, larger than most ranges obtained from microscopic calculations and other nuclear experiments. We use a nonparametric equation of state representation based on Gaussian processes to constrain the symmetry energy S_{0}, L, and R_{skin}^{^{208}Pb} directly from observations of neutron stars with minimal modeling assumptions. The resulting astrophysical constraints from heavy pulsar masses, LIGO/Virgo, and NICER clearly favor smaller values of the neutron skin and L, as well as negative symmetry incompressibilities. Combining astrophysical data with PREX-II and chiral effective field theory constraints yields S_{0}=33.0_{-1.8}^{+2.0} MeV, L=53_{-15}^{+14} MeV, and R_{skin}^{^{208}Pb}=0.17_{-0.04}^{+0.04} fm.

Using Climate-HIV to describe real-world clinical outcomes for people living with HIV taking dolutegravir-based regimens.

OBJECTIVES: The objective of this study was to describe the real-world use and effectiveness of dolutegravir-based regimens (DBRs) in routine clinical practice in the United Kingdom. METHODS: Retrospective analysis was conducted using data from four National Health Service trusts using Climate-HIV, an electronic case record system. Eligible patients were aged ≥18 years with HIV-1 infection who were prescribed a DBR from December 2012 to March 2018. Outcome measurements were accessed at DBR initiation and at weeks 24, 48 and 96 and the last recorded visit up to the extraction date (last measurement). The primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at Week 48. RESULTS: The study cohort included 934 patients; 337 (36%) were female, 414 (47%) were white and 717 (77%) were treatment experienced (TE). The Kaplan-Meier estimated probability of achieving HIV-1 RNA <50 copies/mL at 48 weeks was 96% for treatment-naive (TN) patients and 86% for TE patients. Median times to viral suppression (<50 copies/mL) were 49 and 57 days for TN and TE patients with detectable baseline viral load, respectively, according to Kaplan-Meier analysis. Median follow-up time was 377 days (interquartile range: 131-683). At last measurement, 87% (809/934) of patients remained on a DBR; among those patients, 681 (84%) had HIV-1 RNA <50 copies/mL. CONCLUSIONS: High levels of virologic suppression and low rates of discontinuation of DBRs were seen in a large, diverse, UK-based population with HIV-1 infection. These findings are broadly consistent with efficacy data from phase III studies.

Improved Limits for Higgs-Portal Dark Matter from LHC Searches.

Searches for invisible Higgs decays at the Large Hadron Collider constrain dark matter Higgs-portal models, where dark matter interacts with the standard model fields via the Higgs boson. While these searches complement dark matter direct-detection experiments, a comparison of the two limits depends on the coupling of the Higgs boson to the nucleons forming the direct-detection nuclear target, typically parametrized in a single quantity f_{N}. We evaluate f_{N} using recent phenomenological and lattice-QCD calculations, and include for the first time the coupling of the Higgs boson to two nucleons via pion-exchange currents. We observe a partial cancellation for Higgs-portal models that makes the two-nucleon contribution anomalously small. Our results, summarized as f_{N}=0.308(18), show that the uncertainty of the Higgs-nucleon coupling has been vastly overestimated in the past. The improved limits highlight that state-of-the-art nuclear physics input is key to fully exploiting experimental searches.

Hepatitis B, hepatitis C, and mortality among HIV-positive individuals.

OBJECTIVES: To compare rates of all-cause, liver-related, and AIDS-related mortality among individuals who are HIV-monoinfected with those coinfected with HIV and hepatitis B (HBV) and/or hepatitis C (HCV) viruses. DESIGN: An ongoing observational cohort study collating routinely collected clinical data on HIV-positive individuals attending for care at HIV treatment centres throughout the United Kingdom. METHODS: Individuals were included if they had been seen for care from 2004 onwards and had tested for HBV and HCV. Crude mortality rates (all cause, liver related, and AIDS related) were calculated among HIV-monoinfected individuals and those coinfected with HIV, HBV, and/or HCV. Poisson regression was used to adjust for confounding factors, identify independent predictors of mortality, and estimate the impact of hepatitis coinfection on mortality in this cohort. RESULTS: Among 25 486 HIV-positive individuals, with a median follow-up 4.5 years, HBV coinfection was significantly associated with increased all-cause and liver-related mortality in multivariable analyses: adjusted rate ratios (ARR) [95% confidence intervals (95% CI)] were 1.60 (1.28-2.00) and 10.42 (5.78-18.80), respectively. HCV coinfection was significantly associated with increased all-cause (ARR 1.43, 95% CI 1.15-1.76) and liver-related mortality (ARR 6.20, 95% CI 3.31-11.60). Neither HBV nor HCV coinfection were associated with increased AIDS-related mortality: ARRs (95% CI) 1.07 (0.63-1.83) and 0.40 (0.20-0.81), respectively. CONCLUSION: The increased rate of all-cause and liver-related mortality among hepatitis-coinfected individuals in this HIV-positive cohort highlights the need for primary prevention and access to effective hepatitis treatment for HIV-positive individuals.

Short-Range Correlations and the EMC Effect in Effective Field Theory.

We show that the empirical linear relation between the magnitude of the EMC effect in deep inelastic scattering on nuclei and the short-range correlation scaling factor a_{2} extracted from high-energy quasielastic scattering at x≥1 is a natural consequence of scale separation and derive the relationship using effective field theory. While the scaling factor a_{2} is a ratio of nuclear matrix elements that individually depend on the calculational scheme, we show that the ratio is independent of this choice. We perform Green's function Monte Carlo calculations with both chiral and Argonne-Urbana potentials to verify this and determine the scaling factors for light nuclei. The resulting values for ^{3}He and ^{4}He are in good agreement with experimental values. We also present results for ^{9}Be and ^{12}C extracted from variational Monte Carlo calculations.

Effects of age on antiretroviral plasma drug concentration in HIV-infected subjects undergoing routine therapeutic drug monitoring.

OBJECTIVES: The pharmacokinetic and pharmacodynamic effects of antiretroviral therapy may differ in older compared with younger subjects with HIV infection. We aimed to assess factors associated with plasma antiretroviral drug exposure, including age, within a large HIV-infected cohort undergoing therapeutic drug monitoring (TDM). METHODS: Data from the Liverpool TDM Registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. All TDM of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) was included and in order to account for different antiretroviral drugs the plasma concentrations were standardized by group measurements according to drug, dosing and timing of TDM. Regression modelling was used to evaluate associations of drug exposure with age and clinical parameters, including hepatic transaminase results and time to antiretroviral treatment modification. RESULTS: Data from 3589 TDM samples were available from 2447 subjects. The greatest numbers of plasma concentrations were assessed for lopinavir (22.4%), efavirenz (18.5%), atazanavir (17.0%) and saquinavir (11.6%). As age increased, median standardized NNRTI concentrations remained constant, whereas PI concentrations increased (correlation coefficient 0.04, P = 0.033). In a regression analysis stratified by antiretroviral drug class, standardized plasma concentrations were significantly associated with age for PIs (0.05 increase in standard deviation of drug concentration with each 10 year increase in age, P = 0.044), but not for NNRTIs or other clinical parameters, including hepatic transaminase results or time to antiretroviral treatment modification. CONCLUSIONS: With increasing age, statistically significant rises in plasma PI exposure, but not NNRTI exposure, were observed. The clinical relevance of this observation merits further investigation.

Lower healthcare costs associated with the use of a single-pill ARV regimen in the UK, 2004-2008.

AIM: Investigate the cost and effects of a single-pill versus two- or three pill first-line antiretroviral combinations in reducing viral load, increasing CD4 counts, and first-line failure rate associated with respective regimens at 6 and 12 months. METHODS: Patients on first-line TDF+3TC+EFV, TDF+FTC+EFV, Truvada®+EFV or Atripla® between 1996-2008 were identified and viral load and CD4 counts measured at baseline, six and twelve months respectively. Factors that independently predicted treatment failure at six and twelve months were derived using multivariate Cox's proportional hazard regression analyses. Use and cost of hospital services were calculated at six and twelve months respectively. RESULTS: All regimens reduced viral load to below the limit of detection and CD4 counts increased to similar levels at six and twelve months for all treatment regimens. No statistically significant differences were observed for rate of treatment failure at six and twelve months. People on Atripla® generated lower healthcare costs for non-AIDS patients at £5,340 (£5,254 to £5,426) per patient-semester and £9,821 (£9,719 to £9,924) per patient-year that was £1,344 (95%CI £1,222 to £1,465) less per patient-semester and £1,954 (95%CI £1,801 to £2,107) less per patient-year compared with Truvada®+EFV; healthcare costs for AIDS patients were similar across all regimens. CONCLUSION: The single pill regimen is as effective as the two- and three-pill regimens of the same drugs, but if started as first-line induction therapy there would be a 20% savings on healthcare costs at six and 17% of costs at twelve months compared with Truvada®+EFV, that generated the next lowest costs.

The cost-effectiveness of early access to HIV services and starting cART in the UK 1996-2008.

AIM: To calculate use, cost and cost-effectiveness of people living with HIV (PLHIV) starting routine treatment and care before starting combination antiretroviral therapy (cART) and PLHIV starting first-line 2NRTIs+NNRTI or 2NRTIs+PI(boosted), comparing PLHIV with CD4≤200 cells/mm3 and CD4>200 cells/mm3. Few studies have calculated the use, cost and cost-effectiveness of routine treatment and care before starting cART and starting cART above and below CD4 200 cells/mm3. METHODS: Use, costs and cost-effectiveness were calculated for PLHIV in routine pre-cART and starting first-line cART, comparing CD4≤200 cells/mm3 with CD4>200 cells/mm3 (2008 UK prices). RESULTS: cART naïve patients CD4≤200 cells/mm3 had an annual cost of £6,407 (95%CI £6,382 to £6,425) PPY compared with £2,758 (95%CI £2,752 to £2,761) PPY for those with CD4>200 cells/mm3; cost per life year gained of pre-cART treatment and care for those with CD4>200 cells/mm3 was £1,776 (cost-saving to £2,752). Annual cost for starting 2NRTIs+NNRTI or 2NRTIs+PI(boosted) with CD4≤200 cells/mm3 was £12,812 (95%CI £12,685-£12,937) compared with £10,478 (95%CI £10,376-£10,581) for PLHIV with CD4>200 cells/mm3. Cost per additional life-year gained on first-line therapy for those with CD4>200 cells/mm3 was £4639 (£3,967 to £2,960). CONCLUSION: PLHIV starting to use HIV services before CD4≤200 cells/mm3 is cost-effective and enables them to be monitored so they start cART with a CD4>200 cells/mm3, which results in better outcomes and is cost-effective. However, 25% of PLHIV accessing services continue to present with CD4≤200 cells/mm3. This highlights the need to investigate the cost-effectiveness of testing and early treatment programs for key populations in the UK.

Outcomes in the first year after initiation of first-line HAART among heterosexual men and women in the UK CHIC Study.

BACKGROUND: We analysed the influence of gender on use and outcomes of first-line HAART in a UK cohort. METHODS: Analyses included heterosexuals starting HAART from 1998-2007 with pre-treatment CD4(+) T-cell count<350 cells/mm(3) and viral load (VL)>500 copies/ml. Virological suppression (<50 copies/ml), virological rebound (>500 copies/ml), CD4(+) T-cell counts at 6 and 12 months, clinical events and treatment discontinuation/switch in the first year of HAART were compared using linear, logistic and Cox regression. RESULTS: Compared with women (n=2,179), men (n=1,487) were older and had lower CD4(+) T-cell count and higher VL at start of HAART. Median follow-up was 3.8 years (IQR 2.0-6.2). At 6 and 12 months, 72.7% and 75.3% had VL≤50 copies/ml, with no large differences between genders at either time after adjustment for confounders (6 months, OR 0.92 [95% CI 0.76-1.13]; 12 months, OR 1.06 [95% CI 0.85-1.31]). Overall, 79.4% patients achieved virological suppression and 19.2% experienced virological rebound, without gender differences, although men had an increased risk of rebound after excluding pregnant women (adjusted relative hazard [RH] 1.33 [95% CI 1.04-1.71]). Mean CD4(+) T-cell count increases at 6 and 12 months were, respectively, 112 and 156 cells/mm(3) overall, with mean differences between men and women of -14.6 cells/mm(3) (95% CI -24.6--4.5) and -12.1 cells/mm(3) (95% CI -24.4-0.2) at 6 and 12 months, respectively. Clinical progression was similar in men and women, but men were less likely to experience treatment discontinuation/switch (adjusted RH 0.72 [95% CI 0.63-0.83]). CONCLUSIONS: Despite higher discontinuation rates among women, men had an increased risk of virological rebound and slightly poorer CD4(+) T-cell count responses. Identifying the reasons underlying treatment discontinuation/switch may help optimize treatment strategies for both genders.

Three-body forces and the limit of oxygen isotopes.

The limit of neutron-rich nuclei, the neutron drip line, evolves regularly from light to medium-mass nuclei except for a striking anomaly in the oxygen isotopes. This anomaly is not reproduced in shell-model calculations derived from microscopic two-nucleon forces. Here, we present the first microscopic explanation of the oxygen anomaly based on three-nucleon forces that have been established in few-body systems. This leads to repulsive contributions to the interactions among excess neutrons that change the location of the neutron drip line from (28)O to the experimentally observed (24)O. Since the mechanism is robust and general, our findings impact the prediction of the most neutron-rich nuclei and the synthesis of heavy elements in neutron-rich environments.

Data linkage reduces loss to follow-up in an observational HIV cohort study.

OBJECTIVE: To ascertain the degree of loss to follow-up in a cohort and to identify its predictors. STUDY DESIGN AND SETTING: Human immunodeficiency virus (HIV)-infected individuals without CD4 cell counts for a year or more were defined as potentially lost to follow-up (LFU). Multivariable Poisson regression models identified the risk factors for potential LFU. Multivariable logistic regression models compared demographic and clinical characteristics of those who returned for care and those permanently LFU. RESULTS: Of 16,595 patients under follow-up, 43.6% were potentially LFU at least once. Of these, 39.8% were considered permanently LFU and 60.2% were seen again after 1 year. Of 9,766 episodes when patients were potentially LFU, 59% resulted in the patient returning for care at the same clinic or at a different clinic. Compared with those permanently LFU, patients returning were more likely to have started highly active antiretroviral therapy, to have higher CD4 counts and viral loads, to be younger, and to have had more CD4 tests before LFU. They were less likely to have had a previous episode of potential LFU. CONCLUSIONS: A substantial proportion of patients in the UK Collaborative HIV Cohort study are potentially LFU. Data linkage identifies patients returning for care at different centers. Recognition of factors associated with LFU may help reduce this important source of bias in observational databases.

Late diagnosis in the HAART era: proposed common definitions and associations with mortality.

OBJECTIVE: To identify a definition of presentation after clinical or immunological disease progression that will reliably identify an individual at high risk of mortality over the first 3 months after HIV diagnosis and that can be adopted as a basis for comparing over time and regions. DESIGN: An observational cohort study. METHODS: Individuals seen for the first time at a UK Collaborative HIV Cohort study clinic from 1996 to 2006 were identified. Two immunological (CD4 cell count < 200 cells/microl and CD4 cell count <50 cells/microl) and two clinical (AIDS and severe/moderate AIDS) criteria for presentation with advanced HIV disease were compared, as well as combinations of them. The predictive ability of each diagnosis for identifying individuals who died in the first 3 months after HIV diagnosis was assessed. RESULTS: Fifteen thousand seven hundred and seventy-four patients were included, of whom 1495 (9.5%), 4231 (26.8%), 1523 (9.7%) and 379 (2.4%) had a CD4 cell count below 50 cells/microl, CD4 cell count below 200 cells/microl, AIDS or severe/moderate AIDS at diagnosis; CD4 cell counts were unavailable for 2264 (14.4%) patients. Two hundred and six (1.3%) patients died within the first 3 months. Sensitivities of the individual criteria ranged from 18.0% (severe/moderate AIDS) to 50.5% (CD4 cell count < 200 cells/microl) with specificities ranging from 73.5% (CD4 < 200 cells/microl) to 97.8% (severe/moderate AIDS). Combinations of clinical and immunological criteria increased the sensitivity but decreased the specificity. CONCLUSION: We propose that presentation with 'advanced HIV disease' is presentation with a CD4 cell count below 200 cells/microl or AIDS, whereas 'late' presentation is defined as presentation when the CD4 cell count is below that when treatment should be initiated (currently CD4 cell count < 350 cells/microl or AIDS).

Acute mesenteric ischaemia on unenhanced computer-tomography.

We present a 39-year old man with mesenteric ischaemia. The initial unenhanced images of the, non-oral contrast CT abdomen clearly demonstrated increased density in a significant length of the small bowel and in the veins of the adjacent mesentery. Mesenteric ischaemia is a difficult diagnosis both clinically and radiologically and we demonstrate the potential benefits of an unenhanced abdominal scan (often left out if a contrast enhanced scan is to be performed) and the omission of oral bowel contrast in emergency scans.

Finite-size and confinement effects in spin-polarized trapped Fermi gases.

We calculate the energy of a single fermion interacting resonantly with a Fermi sea of different-species fermions in anisotropic traps, and show that finite particle numbers and the trap geometry impact the phase structure and the critical polarization. Our findings contribute to understanding some experimental discrepancies in spin-polarized Fermi gases as finite-size and confinement effects.

CD4 counts and the risk of systemic non-Hodgkin's lymphoma in individuals with HIV in the UK.

Since the introduction of highly active antiretroviral therapy, there has been a decline in the incidence of non-Hodgkin's lymphoma among HIV-infected individuals. We described trends in the incidence of systemic non-Hodgkin's lymphoma in the UK CHIC Study from 1996-2006 and evaluated the association between immunosuppression and development of systemic non-Hodgkin's lymphoma: 286/23,155 (1.2%) individuals developed an AIDS-defining lymphoma (258 systemic). Younger age, receipt of highly active antiretroviral therapy and later calendar year were all independently associated with a reduced risk of systemic non-Hodgkin's lymphoma. A lower latest CD4 count was strongly associated with systemic non-Hodgkin's lymphoma, in patients who had (RR per log(2)(cells/mm(3)) higher: 0.62) and had not (0.70) received highly active antiretroviral therapy. Associations with other measures of immunosuppression, including nadir CD4 count, experience and duration of severe immunosuppression, were generally weaker. Earlier highly active anti-retroviral therapy initiation and wider access to HIV testing is advocated to reduce the risk of systemic non-Hodgkin's lymphoma.

Treatment switches after viral rebound in HIV-infected adults starting antiretroviral therapy: multicentre cohort study.

OBJECTIVE: To describe the time from first viral rebound on highly active antiretroviral therapy to first treatment change, identify factors associated with more rapid switching, and investigate whether treatment changes are in line with treatment guidelines. DESIGN AND SETTING: A multicentre cohort study. METHODS: We described the time to first treatment switch among individuals experiencing confirmed virological rebound after initiating highly active antiretroviral therapy; factors associated with more rapid switching were identified using proportional hazards regression and predictors of a switch in line with guidelines were identified using logistic regression. RESULTS: Thirty-four percent of the 694 patients experiencing virological rebound remained on a failing regimen for more than 6 months. Factors associated with more rapid switching were lower CD4 cell count (hazard ratio, 0.84 /100 cells/mul higher, P < 0.001), higher viral load (1.29 /log10 copies/ml higher, P < 0.001), older age (1.06 /5 years older, P = 0.07), and changing/adding drugs to the regimen prior to rebound (1.16, P = 0.16). Two hundred and eighteen of the 394 treatment changes (55%) were in line with guidelines; those receiving nonnucleoside reverse transcriptase inhibitor-containing regimens were more likely to make changes in line with guidelines (adjusted odds ratio, 2.80, P < 0.001), whereas those who had previously added drugs to their regimen were less likely to make changes in line with guidelines (0.15, P = 0.001). CONCLUSION: A substantial minority of patients remain on a failing highly active antiretroviral therapy regimen for periods of 6 months or longer without adding new drugs. Changes made are often not in line with treatment guidelines, raising concerns about the development of resistance and long-term clinical outcomes in these individuals.