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Presents data showing that buffalo hump (BH) is associated with physical features of the lipodystrophy phenotype, but not dyslipedemia, and suggests that hyperinsulinemia, a feature common to HIV-associated lipodystrophy (HIVLD), obesity and hypercortisolism, is an important component of this phenotype. Finding that warrants the closer monitoring of BH-positive patients for glucose intolerance and diabetes; Identification of risk factors for a BH in HIV-infected adults in cross-sectional analyses of 2 HIV-infected ambulatory populations.

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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: The purpose of this article is to review alterations in microbiota composition, diversity, and functional features in the context of chronic inflammation and comorbidities associated with HIV infection., Recent Findings: The gut microbiome is an important mediator of host immunity, and disruption of gut homeostasis can contribute to both systemic inflammation and immune activation. Ageing and HIV share features of intestinal damage, microbial translocation and alterations in bacterial composition that contribute to a proinflammatory state and development of age-related comorbidities. One such inflammatory pathway reviewed is the nicotinamide adenine dinucleotide (NAD+) producing kynurenine pathway (KP). Kynurenine metabolites regulate many biological processes including host-microbiome communication, immunity and oxidative stress and the KP in turn is influenced by the microbiome environment. Age-associated decline in NAD+ is implicated as a driving factor in many age-associated diseases, including those seen in people with HIV (PWH). Recent studies have shown that KP can influence metabolic changes in PWH, including increased abdominal adiposity and cardiovascular disease. Furthermore, KP activity increases with age in the general population, but it is elevated in PWH at all ages compared to age-matched controls. Host or microbiome-mediated targeting of this pathway has merits to increase healthy longevity and has potential therapeutic applications in PWH., Summary: As a growing proportion of PWH age, many face increased risks of developing age-related comorbidities. Chronic inflammation, a pillar of geroscience, the science of ageing and of age-related disease, is influenced by the gut microbiome and its metabolites. Combined, these contribute to a systemic inflammatory signature. Advances in geroscience-based approaches and therapeutics offer a novel paradigm for addressing age-related diseases and chronic inflammation in HIV infection. Whether targeted inhibition of KP activity alleviates pathological conditions or promotes successful ageing in PWH remains to be determined., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Cardiovascular diseases (CVD) is one of the leading cause of morbidity and mortality in antiretroviral treated people living with HIV (PWH) with risk score algorithms based on traditional risk factors being shown to be consistently unreliable in estimating risk in this population. This review aims to examine recent data published in last 18-24 months exploring biomarkers that may be useful in identifying PWH at risk of developing CVD., Recent Findings: Ongoing research explores the association of inflammatory biomarkers with subclinical CVD with few studies examining their clinical utility in improving CVD risk prediction. Further mechanistic studies explore the role of monocyte/macrophages in CVD pathogenesis with some studies examining functional assays as better predictors of CVD risk., Summary: Although persistent associations with inflammatory markers and CVD are demonstrated, few biomarkers have emerged as being clinically useful. Large population studies are needed to assess their utility in improving CVD risk prediction in PWH., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: People living with HIV (PWH) are at greater risk of low bone mineral density (BMD) and fractures compared to the general population. This narrative review summarises recent literature in the field, including the relative contribution of antiretroviral therapy and frailty to low BMD and fractures in PWH., Recent Findings: The body of evidence indicating less impact on BMD from the use of tenofovir alafenamide compared to tenofovir disoproxil fumarate continues to grow, although this has not yet translated into data supporting a reduction in fracture incidence. Frailty, common in PWH, is associated with both fractures and alterations in renal-bone metabolism, but is an area that is understudied in relation to interventions to reduce fracture risk in PWH., Summary: Although a maturing field, research into interventions to reduce fracture incidence in PWH is lacking in both quantity and scope. Development of core outcome datasets for clinical trials along with trials focused on reducing or reversing frailty are required to guide improvements overall bone health outcomes in PWH., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine comorbidity indices in people with HIV (PWH) and lifestyle-similar HIV-negative controls., Design: Cross-sectional analysis of the Pharmacokinetic and clinical Observations in PeoPle over fiftY cohort study in the United Kingdom and Ireland., Methods: The Elixhauser Comorbidity Index (ECI), Charlson Comorbidity Index and the Comorbidity Burden Index were compared between older PWH and HIV-negative controls using the Mann-Whitney U test; the magnitude of the difference between groups was quantified using the r effect size., Results: The 699 PWH and 304 HIV-negative controls were predominantly male (87.5% vs. 64.0%), white (86.3% vs. 90.0%) and had median ages of 57 and 58 years, respectively. Among PWH, the median (interquartile range) CD4 T-cell count was 624 (475, 811) cells/μl; 98.7% were on antiretroviral therapy. The median (interquartile range) ECI was 0 (0, 8) and 0 (-3, 1), Charlson Comorbidity Index was 2 (1, 5) and 1 (0, 1) and Comorbidity Burden Index 8.6 (2.2, 16.8) and 5.9 (0.6, 10.8), respectively. While all three indices were significantly higher in PWH than in controls (P < 0.001 for each), the magnitude of the differences between the two groups were small to medium, with effect sizes (95% confidence interval) of 0.21 (0.16, 0.27), 0.38 (0.32, 0.42) and 0.18 (0.11, 0.23), respectively., Conclusion: These three comorbidity indices are higher in PWH compared with HIV-negative controls, although the magnitude of differences between groups were small. Differences in the ECI, reportedly associated with poorer coronavirus disease 2019 outcomes, were driven by more individuals with HIV being within the higher end of the range.

Aims: To assess associations of comorbidity patterns observed in people living with HIV (PLWH) with risk factors and health outcomes., Methods: Common patters of comorbidities in PLWH participating in the Pharmacokinetic and Clinical Observations in People Over Fifty study were determined using principal component analysis and a severity score for each pattern was derived. Associations between each pattern's severity score and risk factors were assessed using median regression. The independent associations of patterns' severity scores with self-reported physical and mental health (SF-36 summary scores) were assessed using linear regression, with functional impairment (Lawton IADL < 8) and hospitalization in last year using logistic regression and with number of general practitioner visits using Poisson regression., Results: A total of 1073 PLWH were analysed: 85.2% male, median (interquartile range) age 52 (47-59) years, 98% on therapy. Duration of HIV was associated with higher severity in 4/6 of patterns: cardiovascular diseases, mental health problems, metabolic disorders and chest/other infections (all P ≤ 0.001). Prior AIDS was associated with higher severity scores for the same patterns and for the pattern of cancers (P < 0.001). The pattern of cardiovascular diseases was associated with poorer physical health (P = 0.02), higher risk of functional impairment (P = 0.02) and hospitalization (P < 0.001) and with higher number of general practitioner visits (P < 0.001). Severity of mental health (all P < 0.001) and of chest/other infections patterns negatively affected all the five health outcomes., Conclusion: Common patterns of comorbidities seen in PLWH appear to have different risk factors and to differently affect health outcomes. These findings may assist the development of targeted intervention to prevent, treat and manage the increasingly prevalent multimorbidity in PLWH.

Objective: We describe the prevalence of pain and its associations with healthcare resource utilization and quality-of-life., Design: The POPPY Study recruited three cohorts: older people living with HIV (PLWH; ≥50 years, n = 699), younger demographically/lifestyle similar PLWH (less than 50 years, n = 374) and older demographically/lifestyle similar HIV-negative (≥50 years, n = 304) people from April 2013 to February 2016., Methods: Current pain and pain-related healthcare use was collected via a self-reported questionnaire. Logistic regression assessed between-group differences in the prevalence of pain in the past month and current pain after controlling for potential confounders. Associations between current pain and healthcare resource use, reported joint problems, depressive symptoms, quality-of-life and functional status were assessed in PLWH using Mann-Whitney U and chi-squared tests., Results: Pain in the past month was reported by 473 out of 676 (70.0%) older PLWH, 224 out of 357 (62.7%) younger PLWH and 188 out of 295 (63.7%) older HIV-negative controls (P = 0.03), with current pain reported in 330 (48.8%), 134 (37.5%) and 116 (39.3%), respectively (P = 0.0007). Older PLWH were more likely to experience current pain, even after adjustment for confounders. Of those with pain in the past month, 56 out of 412 (13.6%) had missed days of work or study due to pain, and 520 (59%) had seen a doctor about their pain. PLWH experiencing current pain had more depressive symptoms, poorer quality-of-life on all domains and greater functional impairment, regardless of age group., Conclusion: Even in the effective antiretroviral therapy era, pain remains common in PLWH and has a major impact on quality-of-life and associated healthcare and societal costs. Interventions are required to assist clinicians and PLWH to proactively manage pain.

Purpose of Review: There is increasing evidence pointing toward an important role of heightened immune activation and inflammation in people living with HIV contributing to the development of non-AIDS comorbidities. This review aims to explore low bone mineral density (BMD) in HIV with a focus on the underlying mechanisms and relationships between the immune and skeletal systems., Recent Findings: Baseline immune activation and inflammation negatively impact BMD at antiretroviral therapy (ART) initiation. B- and T-cell alterations in HIV lead to an imbalance in the osteoblastic osteoprotegerin (OPG) and osteoclastic receptor activator of NF-κB ligand (RANKL) cytokines which favours osteoclastogenesis and bone resorption. These findings suggest an important role for immune-mediated mechanisms in the pathogenesis of low BMD in HIV., Summary: Bone homeostasis is in part regulated by cells of the immune system through complex interactions with the RANK/RANKL/OPG axis. Disturbances in the normal functioning of T, B cells, and monocytes in HIV and the resulting proinflammatory state may contribute to dysregulation of this finely controlled balance leading to increased bone loss. Pre-ART levels of immune activation and inflammation have a consistently negative effect on BMD and further suggest the immunocentric basis of bone loss in HIV alongside supporting the benefits of earlier ART initiation. Further longitudinal studies will help determine the effect this will have on fracture risk in people living with HIV.

Purpose of Review: Osteoporosis remains an important focus of contemporary research in HIV, with co-morbidities and mortality from non-AIDS illnesses now a major barrier to normal lifespan in many populations living with HIV. This review outlines the major recent advances in our understanding of osteoporosis and fractures in those living with HIV and identifies remaining gaps in our knowledge of this complex but increasingly important aspect of aging research in HIV., Recent Findings: Low bone mineral density (BMD), osteoporosis and fractures are all more common in those living with HIV, with recent data pointing for the first time to causal links between low BMD and fractures in those with HIV. The natural history and pathogenesis of osteoporosis in HIV and the epidemiology of fractures in this vulnerable population differ considerably from the general population, with both disease-related and treatment-related factors both contributing to its development through alterations in bone turnover and defects in bone architecture., Summary: Only through a greater understanding of the pathogenesis can appropriate screening and preventive measures be taken in people living with HIV to preserve bone health as they age.

Purpose of Review: Low bone mineral density (BMD) is common in those with HIV, associated with higher bone turnover and a higher prevalence of fractures. This review explores low BMD in HIV, focusing on underlying mechanisms and relationships between low BMD and HIV infection, immune dysfunction, and antiretroviral therapy (ART)., Recent Findings: Greater reductions in BMD accompanying reductions in HIV viremia at initiation of first-line or second-line ART suggest an important role for immune- or viral-mediated mechanisms in its pathogenesis., Summary: As bone metabolism is part-regulated by T cells and B cells, we propose that earlier initiation of ART at higher CD4 T-cell counts may attenuate BMD loss by abrogating immune- and viral-mediated disturbances in bone metabolism that accompany ART initiation. Further pathogenesis-based research is required in this field, focusing on the complex interaction between virus, immune system, ART, and bone metabolism.

Objective: No randomized study has prospectively followed subcutaneous adipose tissue mitochondrial DNA (mtDNA) changes when starting thymidine nucleoside reverse transcriptase inhibitors (tNRTIs)., Design: The Metabolic Effects of DIfferent CLasses of AntiretroviralS study randomized HIV-positive, treatment-naive male participants to start lopinavir/ritonavir (LPVr) with either zidovudine/lamivudine (ZDV/3TC) or nevirapine (NVP)., Methods: Regional body fat was assessed by dual energy x-ray absorptiometry and abdominal computed tomography at months 0, 3, 12, 24 and 36. In a molecular substudy, subcutaneous adipose tissue (SAT) biopsies were taken, with mtDNA quantified by quantitative PCR. Data were analyzed using repeated measures linear regression analyses., Results: Of 50 participants recruited (23 to LPVr/ZDV/3TC), 48 started therapy, and 37 participants (19 on LPVr/ZDV/3TC) enrolled in the substudy. At 36 months, the LPVr/ZDV/3TC group had significantly lower limb fat [6.4 kg (0.26) versus 7.3 kg (0.31), P = 0.017] and a trend toward lower abdominal SAT compared to the LPVr/NVP group [131 cm (6.86) versus 146 cm (6.33), P = 0.097]. Over 36 months, mtDNA declined in the LPVr/ZDV/3TC group [mtDNA region 1: -190 (95) copies/cell, P = 0.053, region 2: -269 (106) copies/cell, P = 0.016] but not within the LPVr/NVP group [region 1: +28 (99) copies/cell, P = 0.78, region 2: +51 (111) copies/cell, P = 0.65, between-group difference P < 0.01 for both measurements]. mtDNA was significantly lower in the LPVr/ZDV/3TC group at 36 months., Conclusion: This is the first randomized study to prospectively demonstrate reductions in SAT mtDNA in patients initiating ZDV/3TC-containing antiretroviral therapy (ART) but not in those initiating nucleoside reverse transcriptase inhibitor-sparing ART containing NVP and protease inhibitor. That reductions in SAT mtDNA were also accompanied by lower limb fat suggests that use of ART not containing ZDV/3TC may help prevent development of peripheral lipoatrophy.

We aimed to determine the contribution of high-density lipoprotein cholesterol (HDL-c) to cardiovascular disease (CVD) risk in a cohort of HIV-infected patients. The contribution of CVD risk factors to the predicted CVD risk was assessed. We estimated the degree of reclassification of CVD risk if HDL-c concentration was increased in all patients by 20 and 40%, respectively. After age, HDL-c contributed most to the overall cardiovascular risk. Increasing HDL-c by 20% and 40% reclassified six and 12 patients to lower CVD risk groups, respectively. In this cohort, HDL-c contributed more to cardiovascular risk than smoking, total cholesterol, systolic blood pressure (SBP) and sex.

Objective: Cardiovascular disease and myocardial infarction are of increasing concern in HIV-infected populations. Although platelets mediate arterial thrombosis, central to myocardial infarction, data on platelet function in HIV infection are lacking. We hypothesized that HIV-infected patients would have altered platelet reactivity., Design: A case-control study of platelet reactivity in 20 HIV-infected (HIVpos) and 20 age and sex-matched HIV-negative (HIVneg) individuals., Methods: Time-dependent platelet aggregation was measured in response to increasing concentrations of platelet agonists: epinephrine, collagen, thrombin receptor-activating peptide and ADP using light absorbance., Results: In both groups, mean age was 34 years, and 65% were men. Sixteen out of 20 (80%) of the HIVpos patients were on antiretroviral therapy with 12 out of 20 (60%) patients having HIV RNA less than 50 copies/ml. There were significant between-group differences in platelet reactivity across all four agonists. Platelets from HIVpos patients were more reactive to epinephrine [mean (SD) log concentration required to induce 50% maximal aggregation, 1.9 (1.2) versus 3.0 (1.7) mumol/l in HIVneg individuals, P = 0.028], whereas less platelet aggregation was observed in response to submaximal concentrations of the other agonists [thrombin receptor-activating peptide 72.5 (14.5)% versus 82.2 (7.6)% at 10 mumol/l, P = 0.011; ADP 67.3 (12.1)% versus 75.2 (8.8)% at 10 mumol/l, P = 0.035; collagen 16.6 (25.1)% versus 35.4 (31.5)% at 71.25 microg/ml, P = 0.007]., Conclusion: Between-group differences in platelet responses to all agonists suggest multiple underlying defects in platelet function in HIV infection. Further research is required to determine the contribution of antiretroviral therapy and relationships between platelet function and the increased cardiovascular disease observed in HIV-infected populations.

Purpose of Review: This review details the clinical aspects and pathogenesis of low bone mineral density (BMD) in HIV, discusses broad management issues and outlines areas in which our understanding of this condition is incomplete., Recent Findings: Low BMD is prevalent in HIV-infected patients, with traditional risk factors, HIV infection and exposure to antiretroviral therapy all contributing. The role of specific antiretrovirals in the development of low BMD remains controversial, but most changes arise at either antiretroviral therapy initiation or switch., Summary: Further research is needed to clarify mechanisms underlying low BMD in HIV, whether low BMD will translate to increased fractures and to determine the correct therapeutic approach to low BMD in HIV, particularly in younger HIV-infected patients.

Purpose of Review: To describe the clinical features, pathogenesis and therapeutic options for the dyslipidaemia commonly seen in HIV-infected patients on combination antiretroviral therapy., Recent Findings: Dyslipidaemia associated with antiretroviral therapy is characterized by elevations in total and low-density lipoprotein-cholesterol and triglycerides, and decreased high-density lipoprotein-cholesterol - a profile with atherogenic potential. Although a multifactorial cause underlies antiretroviral therapy-associated dyslipidaemia, exposure to all three principal classes of antiretroviral medications - protease inhibitors in particular - has been implicated in its development. Protease inhibitors have been shown to affect several molecular pathways important for lipid metabolism, including intranuclear transcription factors and the nuclear proteasome. Although treatment options are limited, with many conventional therapeutic strategies less effective in the presence of ongoing antiretroviral therapy exposure, the increased incidence of cardiovascular disease observed in some HIV-infected cohorts underlies the need for effective management strategies for antiretroviral therapy-associated dyslipidaemia., Summary: Although use of protease inhibitors is implicated in antiretroviral therapy-associated dyslipidaemia, the extent to which individual protease inhibitors cause dyslipidaemia varies considerably within this drug class. More research is needed to design better tolerated antiretrovirals and improved therapeutic interventions for this common condition.

Objectives: To determine the effect of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin, on markers of cardiovascular risk and lipodystrophy in HIV-infected, protease inhibitor (PI)-treated men with hypercholesterolaemia., Methods: A randomized, placebo-controlled, 16-week study was carried out on 33 HIV-infected, hypercholesterolaemic men (fasting total cholesterol > 6.5 mmol/L) on PI-containing therapy. Patients commenced dietary assessment and advice at week 0 and were randomized to 12 weeks pravastatin (40 mg each night) or placebo from week 4. The primary endpoint was the time-weighted change (TWAUC) in total cholesterol from week 0. Secondary endpoints included TWAUC cholesterol from week 4 (start of pravastatin), total and regional body fat, fasting lipids, glucose, insulin, and markers of cardiovascular risk., Results: Of 33 men randomized (pravastatin n = 16, mean age 48 years), 31 completed the study. Groups were matched for baseline cholesterol and body composition. Although there was no significant between-group difference in TWAUC cholesterol from week 0 (pravastatin -0.6 +/- 1.0 versus placebo -0.4 +/- 1.0 mmol/L/week; P = 0.8), TWAUC cholesterol from week 4 decreased more in the pravastatin group (-0.8 +/- 1.0 versus -0.3 +/- 0.9 mmol/L/week; P = 0.04). Neither triglycerides nor dietary intake changed. Subcutaneous fat increased significantly with pravastatin (+0.72 +/- 1.55 versus +0.19 +/- 0.48 kg change in limb fat, P < 0.04; +5.2 +/- 8.7 versus -1.3 +/- 13.7 cm change in abdominal subcutaneous fat, P = 0.02). Apart from homocystine, which decreased in the pravastatin group, there were no significant differences in other cardiovascular, lipid or glucose parameters., Conclusions: Despite limited effects on cholesterol, 12 weeks use of pravastatin 40 mg each night in HIV-infected men with hypercholesterolaemia resulted in significant increases in subcutaneous fat.