Hepatic steatosis in people older and younger than fifty who are living with HIV and HIV-negative controls: A cross-sectional study nested within the POPPY cohort.

BACKGROUND: Hepatic steatosis is a major cause of chronic liver disease associated with several negative health outcomes. We compared the prevalence of and factors associated with steatosis in people living with and without HIV. METHODS: Older (>50 years) and younger (<50 years) people with HIV and older HIV-negative controls (>50 years) underwent liver transient elastography examination with controlled attenuation parameter (steatosis ≥238 dB/m, moderate/severe steatosis ≥280 dB/m, liver fibrosis ≥7.1 kPa). We compared groups using logistic regression/Chi-squared/Fisher's exact/Kruskal-Wallis tests. RESULTS: In total, 317 participants (109 older people with HIV; 101 younger people with HIV; 107 HIV-negative controls) were predominantly white (86%) and male (76%), and 21% were living with obesity (body mass index ≥30 kg/m2 ). Most (97%) people with HIV had undetectable HIV RNA. The prevalence of fibrosis was 8.4%, 3.0%, and 6.5% in the three groups, respectively (p = 0.26). Fibrosis was predominately (>65%) mild. The prevalence of steatosis was the same in older people with HIV (66.4%) and controls (66.4%) but lower in younger people with HIV (37.4%; p < 0.001). After adjustment, younger people with HIV were less likely to have steatosis (odds ratio [OR] 0.26; 95% confidence interval [CI] 0.14-0.52) than controls, but male sex (OR 2.45; 95% CI 1.20-4.50) and high waist-to-hip ratio (OR 3.04; 95% CI 1.74-5.33) were associated with an increased odds of steatosis. We found no association between steatosis and HIV-related variables. CONCLUSIONS: The prevalence of hepatic steatosis and fibrosis was similar between older participants regardless of HIV status. Age, sex, and abdominal obesity, but not HIV-related variables, were associated with steatosis. Interventions for controlling obesity should be integrated into routine HIV care.

Developing a Bayesian adaptive design for a phase I clinical trial: a case study for a novel HIV treatment.

The design of phase I studies is often challenging, because of limited evidence to inform study protocols. Adaptive designs are now well established in cancer but much less so in other clinical areas. A phase I study to assess the safety, pharmacokinetic profile and antiretroviral efficacy of C34-PEG4 -Chol, a novel peptide fusion inhibitor for the treatment of HIV infection, has been set up with Medical Research Council funding. During the study workup, Bayesian adaptive designs based on the continual reassessment method were compared with a more standard rule-based design, with the aim of choosing a design that would maximise the scientific information gained from the study. The process of specifying and evaluating the design options was time consuming and required the active involvement of all members of the trial's protocol development team. However, the effort was worthwhile as the originally proposed rule-based design has been replaced by a more efficient Bayesian adaptive design. While the outcome to be modelled, design details and evaluation criteria are trial specific, the principles behind their selection are general. This case study illustrates the steps required to establish a design in a novel context. Copyright © 2016 John Wiley & Sons, Ltd.

Association between inflammatory biomarker profiles and cardiovascular risk in individuals with and without HIV.

BACKGROUND: People with HIV have an increased risk for cardiovascular morbidity and mortality. Inflammation and immune activation may contribute to this excess risk. METHODS: We assessed thirty-one biomarkers in a subset of POPPY participants and identified three distinct inflammatory profiles: 'gut/immune activation', 'neurovascular', and 'reference' (relatively low levels of inflammation). Ten-year cardiovascular disease (CVD) risk predictions were calculated using the QRISK, Framingham Risk Score (FRS) and the Data Collection on Adverse effects of anti-HIV Drugs (D:A:D) algorithms. The distributions of CVD risk scores across the different inflammatory profiles, stratified by HIV status, were compared using median quantile regression. RESULTS: Of the 312 participants included [70% living with HIV, median (interquartile range; IQR) age 55 (51-60) years; 82% male; 91% white], 36, 130, and 146 were in the 'gut/immune activation', 'neurovascular', and 'reference' cluster, respectively. The median (IQR) QRISK scores were 9.3% (4.5-14.5) and 10.2% (5.5-16.9) for people with and without HV, respectively, with similar scores obtained with the FRS and D:A:D. We observed statistically significant differences between the distributions of scores in the three clusters among people with HV. In particular, median QRISK [5.8% (1.0-10.7) and 3.1% (0.3-5.8)] scores were higher, respectively, for those in the 'gut/immune activation' and 'neurovascular' clusters compared to those in the reference cluster. CONCLUSIONS: People with HIV with increased gut/immune activation have a higher CVD risk compared to those with relatively low inflammation. Our findings highlight that clinically important inflammatory subgroups could be useful to differentiate risk and maximise prediction of CVD among people with HIV.

Biomarker associations with insomnia and secondary sleep outcomes in persons with and without HIV in the POPPY-Sleep substudy: a cohort study.

STUDY OBJECTIVES: We investigated associations between inflammatory profiles/clusters and sleep measures in people living with HIV and demographically-/lifestyle-similar HIV-negative controls in the Pharmacokinetic and clinical Observations in PeoPle over fiftY (POPPY)-Sleep substudy. METHODS: Primary outcome was insomnia (Insomnia Severity Index [ISI]>15). Secondary sleep outcomes included 7-day actigraphy (e.g. mean/standard deviation of sleep duration/efficiency), overnight oximetry (e.g. oxygen desaturation index [ODI]) and patient-reported measures (Patient-Reported Outcomes Measurement Information System (PROMIS) sleep questionnaires). Participants were grouped using Principal Component Analysis of 31 biomarkers across several inflammatory pathways followed by cluster analysis. Between-cluster differences in baseline characteristics and sleep outcomes were assessed using Kruskal-Wallis/logistic regression/Chi-squared/Fisher's exact tests. RESULTS: Of the 465 participants included (74% people with HIV, median [interquartile range] age 54 [50-60] years), only 18% had insomnia and secondary sleep outcomes suggested generally good sleep (e.g. ODI 3.1/hr [1.5-6.4]). Three clusters with distinct inflammatory profiles were identified: "gut/immune activation" (n = 47), "neurovascular" (n = 209), and "reference" (relatively lower inflammation; n = 209). The "neurovascular" cluster included higher proportions of people with HIV, obesity (BMI>30 kg/m2), and previous cardiovascular disease, mental health disorder, and arthritis of knee/hip relative to the other two clusters. No clinically relevant between-cluster differences were observed in proportions with insomnia (17%, 18%, 20%) before (p = .76) or after (p = .75) adjustment for potential confounders. Few associations were observed among actigraphy, oximetry, and PROMIS measures. CONCLUSIONS: Although associations could exist with other sleep measures or biomarker types not assessed, our findings do not support a strong association between sleep and inflammation in people with HIV.

Agreement between self-reported and objective measures of sleep in people with HIV and lifestyle-similar HIV-negative individuals.

OBJECTIVES: The aim of this study was to evaluate the agreement between self-reported sleep measures and insomnia with objectively measured sleep parameters in people with HIV (PWH) and HIV-negative individuals. DESIGN: A cross-sectional analysis of PWH and lifestyle-similar HIV-negative individuals. METHODS: Self-reported measures included time spent in bed, sleep onset latency and a validated insomnia questionnaire. Objective measures were assessed via 7-days/nights of actigraphy data to determine average and intra-individual variability of several sleep measures (including time spent in bed and onset latency). Spearman's correlation coefficient and Cohen's κ were used to assess the agreement between self-reported and actigraphy-assessed measures. Associations between insomnia and actigraphy-assessed sleep parameters were evaluated using partial least-square discriminant analysis (PLS-DA). RESULTS: We found fair correlation between self-reported and actigraphy-assessed time spent in bed in 342 PWH (rs = 0.46) and 119 HIV-negative individuals (rs = 0.48). Among PWH, the correlation did not differ by age, education, depressive symptoms and self-reported insomnia (all P > 0.05), but was stronger in men (P = 0.05) and in those with a BMI of at least 25 kg/m2 (P < 0.001). Agreement between self-reported and actigraphy-assessed sleep onset latency was poor in both PWH (κ = 0.002, P = 0.49) and HIV-negative individuals (κ = 0.009, P = 0.65). According to PLS-DA, self-reported insomnia most strongly correlated with intra-individual variability of sleep duration, movement index and efficiency. CONCLUSION: We report poor-to-fair agreement between self-reported and actigraphy-assessed sleep measures in PWH. Insomnia symptoms correlated with regularity of sleep duration, quality and efficiency. These findings highlight the importance of both patient-reported and objective measures of daily sleep variation, for better understanding sleep disorders in PWH.

Sleep Disorders in Human Immunodeficiency Virus: A Substudy of the Pharmacokinetics and Clinical Observations in People Over Fifty (POPPY) Study.

BACKGROUND: Self-reported sleep quality is poor in persons with human immunodeficiency virus (PWH), but prior studies commonly used nonspecific questionnaires, investigated only single sleep disorders, or lacked human immunodeficiency virus (HIV)-negative controls. We addressed these limitations in the Pharmacokinetics and Clinical Observations in People Over Fifty (POPPY) Sleep Substudy by assessing PWH and HIV-negative controls for insomnia, restless legs syndrome (RLS), and sleep apnea (SA). METHODS: Previously enrolled POPPY participants coenrolled in this substudy without regard to sleep symptoms. Participants completed validated sleep assessments including the Insomnia Severity Index questionnaire, International Restless Legs Syndrome Study Group questionnaire, and in-home, wrist-worn overnight oximetry. They also completed health-related quality of life questionnaires including 36-item Short Form (SF-36) and Patient-Reported Outcomes Measurement Information System (PROMIS) sleep questionnaires. RESULTS: We enrolled 357 PWH (246 >50 years of age; 111 between 18 and 50 years) and 126 HIV-negative controls >50 years of age. Among PWH, criteria were met by 21% for insomnia, 13% for RLS, and 6% for SA. Compared with HIV-negative controls, PWH had a higher risk of insomnia (adjusted odds ratio, 5.3; 95% confidence interval, 2.2-12.9) but not RLS or SA. Compared with PWH without insomnia, those with insomnia reported significantly worse scores on all SF-36 and PROMIS components; fewer than 30% reported previous diagnosis or treatment for insomnia. CONCLUSIONS: Insomnia was more common in PWH, associated with worse health-related quality of life, and frequently undiagnosed. Further research should focus on the pathogenesis of insomnia in PWH and the development of effective screening and intervention strategies for this unique population.

Sleep health and cognitive function among people with and without HIV: the use of different machine learning approaches.

STUDY OBJECTIVES: We investigated associations between actigraphy-assessed sleep measures and cognitive function in people with and without HIV using different analytical approaches to better understand these associations and highlight differences in results obtained by these approaches. METHODS: Cognitive and 7-day/night actigraphy data were collected from people with HIV (PWH) and lifestyle-similar HIV-negative individuals from HIV and sexual health clinics in the United Kingdom/Ireland. A global cognitive T-score was obtained averaging the standardized individual cognitive test scores accounting for sociodemographics. Average and SD of 11 sleep measures over 7 days/nights were obtained. Rank regression, partial least-squares (PLS) regression, random forest, sleep dimension construct, and latent class analysis (LCA) were applied to evaluate associations between global T-scores and sleep measures. RESULTS: In 344 PWH (median age 57 years, 86% males), average sleep duration, efficiency, and wake after sleep onset were not associated with global T-scores according to rank regression (p = 0.51, p = 0.09, p = 0.16, respectively). In contrast, global T-scores were associated with average and SD of length of nocturnal awakenings, SD of maintenance efficiency, and average out-of-bed time when analyzed by PLS regression and random forest. No associations were found when using sleep dimensions or LCA. Overall, findings observed in PWH were similar to those seen in HIV-negative individuals (median age 61 years, 67% males). CONCLUSIONS: Using multivariable analytical approaches, measures of sleep continuity, timing, and regularity were associated with cognitive performance in PWH, supporting the utility of newer methods of incorporating multiple standard and novel measures of sleep-wake patterns in the assessment of health and functioning.

Associations Between Widespread Pain and Sleep Quality in People With HIV.

BACKGROUND: We investigate the association of widespread pain with sleep quality among people with HIV and HIV-negative controls. SETTING: UK-based cohort. METHODS: Pain information was collected through a pain mannikin identifying affected body sites; pain was classified as widespread if pain was reported in ≥4 of 5 body regions and in ≥7 of 15 body sites, and as regional otherwise. Sleep was assessed a median of 3.2 years later through 7-night actigraphy and through self-reported assessments of sleep quality. Chi-squared tests, Kruskal-Wallis tests, and linear/logistic regression considered associations between pain extent and sleep quality. RESULTS: Of the 414 participants, 74 (17.9%) reported widespread and 189 (45.7%) regional pain. Although there were few clear associations between actigraphy outcomes and pain extent, those with widespread and regional pain consistently reported poorer sleep quality on all self-reported measures than those with no pain. Median (interquartile range) insomnia severity index and Patient-reported Outcomes Measurement Information System (PROMIS) for sleep disturbance and sleep-related impairment scores were 12 (7-16), 55.3 (48.0-58.9), and 57.2 (48.9-61.3), respectively, for those with widespread pain, 8 (4-13), 51.2 (45.5-58.3), and 50.3 (43.6-56.1) for those with regional pain, and 5 (2-9), 47.9 (42.9-54.3), and 45.5 (41.4-50.3) for those with no pain (all P values 0.0001). Associations remained strong after adjustment for HIV status and other confounders, and were reduced but remained significant, after adjustment for depressive symptoms. CONCLUSIONS: Widespread pain was not associated with objective measures of sleep but was strongly associated with self-reported assessments of sleep quality in people with HIV.

A first-in-human study of the novel HIV-fusion inhibitor C34-PEG4-Chol.

Long-acting injectable antiretroviral (LA-ARV) drugs with low toxicity profiles and propensity for drug-drug interactions are a goal for future ARV regimens. C34-PEG4-Chol is a novel cholesterol tagged LA HIV-fusion-inhibitor (FI). We assessed pre-clinical toxicology and first-in-human administration of C34-PEG4-Chol. Pre-clinical toxicology was conducted in 2 species. HIV-positive men were randomised to a single subcutaneous dose of C34-PEG4-Chol at incrementing doses or placebo. Detailed clinical (including injection site reaction (ISR) grading), plasma pharmacokinetic (time-to-minimum-effective-concentration (MEC, 25 ng/mL) and pharmacodynamic (plasma HIV RNA) parameters were assessed. In both mice and dogs, no-observed-adverse effect level (NOAEL) was observed at a 12 mg/kg/dose after two weeks. Of 5 men enrolled, 3 received active drug (10 mg, 10 mg and 20 mg). In 2 individuals grade 3 ISR occurred and the study was halted. Both ISR emerged within 12 hours of active drug dosing. No systemic toxicities were observed. The time-to-MEC was >72 and >96 hours after 10 and 20 mg dose, respectively, and mean change in HIV RNA was -0.9 log10 copies/mL. These human pharmacodynamic and pharmacokinetic data, although limited to 3 subjects, of C34-PEG-4-Chol suggest continuing evaluation of this agent as a LA-ARV. However, alternative administration routes must be explored.