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Background: In Côte d’Ivoire, people living with HIV (PLHIV) have free access to antiretroviral therapy (ART) and cotrimoxazole. Yet, they may use other medications to treat non-HIV diseases. Scarce data are available regarding the use of non-HIV medications in Africa. This study describes the use of non-HIV medications and identifies the factors associated with their use by PLHIV on ART in Côte d’Ivoire. Methods: A cross-sectional study was conducted in six HIV clinics in 2016. HIV-1-infected adults receiving ART for at least one year were eligible. A standardized questionnaire was used to collect demographics, HIV characteristics and medication use data. Associated factors were identified using a multivariate adjusted Poisson regression. Results: A total of 1,458 participants (74% women) were enrolled. The median age was 44 years, and the median duration of ART was 81 months. A total of 696 (48%) participants reported having used at least one non-HIV medication. Among the 1,519 non-HIV medications used, 550 (36%) had not been prescribed and 397 (26%) were from the nervous system class. Individuals who were more likely to report the use of at least one non-HIV medication included those who had been treated in an Abidjan HIV clinic, had a high school education level, had a monthly income between 152 and 304 euros, had a poor perceived health status, had WHO advanced clinical stage, had used traditional medicine products and had not used cotrimoxazole. Conclusion: Almost half PLHIV on ART reported using non-HIV medication. Further research is needed to assess whether the use of non-HIV medication is appropriate given about a third of those medications are not being prescribed. [ABSTRACT FROM AUTHOR]

Background: Inflammation has been associated with increased morbidity and mortality in HIV-positive patients. We compared inflammatory biomarkers with dual therapy using lopinavir/ritonavir plus lamivudine (LPV/r+3TC) versus triple therapy using LPV/r plus two nucleoside reverse transcriptase inhibitors (LPV/r+2NRTIs) in treatment-naïve HIV-positive adults. Methods: This was a substudy among Argentinian participants in the randomized trial GARDEL. We measured hsCRP, IL-6, MCP-1, TNF, D-dimer and sCD14 from plasma collected at baseline, week 24 and week 48. Generalized estimating equations with an identity/logit link were used to model the average impact of dual versus triple therapy on each biomarker over time, controlling for baseline levels. Additional models estimated the average effect of virologic suppression on biomarker levels over time, adjusting for age, sex, and baseline CD4 count. Results: Of 191 trial participants enrolled in Argentina, 172 had baseline and follow-up measurements and were included. Median (IQR) age was 35.5 (28.5, 45) years and CD4 cell count was 310 (219, 414) cells/mm3. Dual therapy was not associated with significantly different biomarker levels over 48 weeks relative to triple therapy. Virologic suppression was associated with statistically significant decreases in MCP-1, TNF and D-dimer levels and an unexpected increase in sCD14 levels. No change was observed in hsCRP or the proportion of participants with undetectable IL-6 levels. Conclusions: In addition to having virologic non-inferiority, LPV/r+3TC dual therapy is generally associated with similar inflammatory biomarker levels over 48 weeks compared to LPV/r+2NRTIs triple therapy in treatment-naïve adults. Further study of dual treatment regimens is warranted. [ABSTRACT FROM AUTHOR]

Introduction: Pneumonia is an important cause of morbidity and mortality in persons living with human immunodeficiency virus (HIV) infection. How immune activation differs among HIV-infected and HIV-uninfected adults with pneumonia is unknown. Methods: The Inflammation, Aging, Microbes, and Obstructive Lung Disease (I AM OLD) Cohort is a prospective cohort of adults with pneumonia in Uganda. In this cross-sectional analysis, plasma was collected at pneumonia presentation to measure the following 12 biomarkers: interleukin 6 (IL-6), soluble tumor necrosis factor receptors 1 and 2 (sTNFR-1 and sTNFR-2), high sensitivity C-reactive protein (hsCRP), fibrinogen, D-dimer, soluble CD27 (sCD27), interferon gamma-inducible protein 10 (IP-10), soluble CD14 (sCD14), soluble CD163 (sCD163), hyaluronan, and intestinal fatty acid binding protein. We asked whether biomarker levels differed between HIV-infected and HIV-uninfected participants, and whether higher levels of these biomarkers were associated with mortality. Results: One hundred seventy-three participants were enrolled. Fifty-three percent were HIV-infected. Eight plasma biomarkers—sTNFR-1, sTNFR-2, hsCRP, D-dimer, sCD27, IP-10, sCD14, and hyaluronan—were higher among participants with HIV infection, after adjustment for pneumonia severity. Higher levels of 8 biomarkers—IL-6, sTNFR-1, sTNFR-2, hsCRP, IP-10, sCD14, sCD163, and hyaluronan—were associated with increased 2-month mortality. Conclusions: As in other clinical contexts, HIV infection is associated with a greater degree of immune activation among Ugandan adults with pneumonia. Some of these are also associated with short-term mortality. Further study is needed to explore whether these biomarkers might predict poor long-term outcomes—such as the development of obstructive lung disease—in patients with HIV who have recovered from pneumonia. [ABSTRACT FROM AUTHOR]

Background: Patients with HIV infection suffer from accelerated aging. In this context, frailty could be a relevant problem that aggravates the quality of life (QoL) and morbi-mortality of these patients. Our objective was to determine the prevalence of frailty and pre-frailty in HIV-infected patients in our cohort as well as their risk factors and QoL. Methods: This was a prospective cross-sectional study of HIV-infected people aged ≥18 years on a stable antiretroviral regimen (ART) ≥1 year. Frailty was defined by ≥3 of 5 Fried's criteria: weight loss, low physical activity, exhaustion, weak grip strength and slow walking time. Variables related to sociodemographics, HIV infection, comorbidities, polypharmacy, and QoL were evaluated. Independent predictors of frailty were evaluated using collinearity in a multivariate logistic regression analyses (backward stepwise elimination). Results: The 248 people studied has a mean age of 49 years, 63.7% were male, and 81% were Caucasian. The prevalence of pre-frailty and fragility was 39.1% and 4.4%, respectively. The main route of HIV acquisition was heterosexual (47.2%). At the inclusion time 26.6% of the patients had AIDS events, 60.9% were anti-HCV negative, and 91.5% had HIV RNA <50 copies/mL (84.3% for ≥1 year); 10.9% had >2 comorbidities, and 13.3% were receiving >5 non-HIV drugs. Frailty patients had a higher age (p 0.006), more sensitive deficits (visual or auditory) (p 0.002), a greater number of falls during the previous year (p 0.0001), a higher Charlson comorbidity index (p 0.001), and a higher VACS index (p 0.001). All comorbidities, excluding bone and liver, were significantly more frequent in fragile patients. The presence of >2 comorbidities and treatment with >5 drugs not related to HIV they were also more frequent in frail patienst (p 0.0001 and p 0.004, respectively). Independent predictors of pre-frailty/frailty in the multivariable analysis differ in men (VACS index, C-reactive protein [CRP], and falls) and women (CRP, AIDS, and menopause). Patients with pre-frailty/frailty had some indicator of a lower QoL. Conclusion: Factors associated with pre-frailty/frailty in HIV-infected patients differ by gender, which should be considered when establishing measures for prevention. The role of menopause in the risk of pre-frailty/frailty warrants further investigations. [ABSTRACT FROM AUTHOR]

Introduction: Increased prevalence of low bone mineral density (BMD) and increased fracture incidence are observed in persons living with HIV (PLWH). The trabecular bone score (TBS) is a novel index of bone microarchitecture which improves fracture prediction independent of BMD. Methods: The HIV UPBEAT study is a single centre, prospective cohort study that enrolled subjects with and without HIV from similar sociodemographic backgrounds for annual assessments of bone health. TBS was derived from lumbar spine (LS) dual-energy X-ray absorptiometry images. Univariate and multivariable linear regression was used to assess relationships between baseline TBS, BMD, sociodemographic and clinical factors. Results: 463 subjects (201 HIV positive) were included; PLWH were younger and more likely male, of non-African ethnicity and current smokers. HIV was associated with a mean reduction of 0.037 [-0.060, -0.013] (p = 0.002) in TBS. Lower TBS was also associated with male gender, non-African ethnicity, current smoking status and lower LS BMD. HIV remained associated with lower TBS after adjustment for LS BMD, age, gender and ethnicity. However, adjustment for current smoking significantly attenuated the association between HIV and TBS, with further adjustment for higher bone turnover markers largely explaining any residual association. Among the sub-group of PLWH, exposure to protease inhibitors and lower nadir CD4+ T-cell counts were both predictors of lower TBS. Conclusions: PLWH have lower TBS independent of LS BMD. However, this is largely explained by higher current smoking rates and higher bone turnover in those with HIV. Exposure to PI, but not tenofovir disproxil fumarate, also contributed to lower TBS in those with HIV. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between current CD4+ T-cell count and CD4/CD8+ ratio with severity of frailty among people aging with HIV. Methods: Cross-sectional observational study analysing data from all study visits in the ongoing prospective Modena HIV Metabolic Clinic Cohort between 2006 and 2015. Frailty severity was assessed using a frailty index (FI). We visualized the relationships between frailty index score and current CD4 cell count and CD4/CD8 ratio on two different curves adjusted for age, sex, and duration of HIV infection. Results: Frailty index scores exhibited an inverse relationship with current CD4 count, up to 900 cells/μL. The CD4/CD8 ratio was inversely correlated with frailty index both below and above the cut-off of 900 CD4 cells/μL. Conclusions: Frailty in PLWH is inversely associated with both immune-activation, depicted by CD4/CD8 ratio and immune-deficit depicted by CD4 count. The first association shows a linear shape while the second shows a hook-shape with a turning point at 900 cells. Above this cut off level CD4 do not represent a significant risk factor for frailty. [ABSTRACT FROM AUTHOR]

HIV infection causes the progressive depletion of CD4+ T-lymphocytes and profound modifications of T-cell homeostasis, which persist despite virologically-suppressive treatment and have been linked to a worse clinical outcome. Enduring alterations of the gastrointestinal tract may represent the underlying pathogenic mechanisms of these phenomena. Twenty-six HIV-infected subjects were assessed over a 12-month period following the introduction of antiretroviral therapy. 18 uninfected individuals were enrolled as controls. Parameters of peripheral T-cell homeostasis (activation, maturation), gastrointestinal function (microbial translocation, gut inflammation, fecal microbiota composition) and mucosal immunity (CD4+CCR6+CD161+, CD4+CCR9+α4β7+, stem cell memory CD4+/CD8+ T-cells) were assessed. CD4+CCR6+CD161+ cells were depleted in HIV-infected untreated subjects and maintained significantly lower levels compared to controls, despite the introduction of effective antiviral treatment. The frequency of gut-homing CD4+CCR9+α4β7+ cells was also impaired in untreated infection and correlated with the HIV RNA load and CD4+HLADR+CD38+; during therapy, we observed a contraction of this pool in the peripheral blood and the loss of its correlation with antigenic exposure/immune activation. A partial correction of the balance between stem cell memory pools and T-cell homeostasis was registered following treatment. In HIV-infected subjects with moderate immune-suppression, antiretroviral therapy has a marginal impact on mucosal immune populations which feature distinctive kinetics in the periphery, possibly reflecting their diverse recruitment from the blood to the mucosa. The persistent defects in mucosal immunity may fuel peripheral T-cell abnormalities through diverse mechanisms, including the production of IL-17/IL-22, cellular permissiveness to infection and regulation of T-lymphocyte maturation. [ABSTRACT FROM AUTHOR]

Objective: People living with HIV (PLWH) are living longer and developing comorbidities and aging-related syndromes. New care models are needed to address the combined burden and complexity of HIV and its comorbidities in this group. The goal of this study is to describe qualitative data from patients and providers that informed the development of a comprehensive care model for older PLWH. Methods: Patient and provider perspectives on the clinical care and service needs of patients living and aging with HIV were explored via surveys and focus groups at a safety net HIV clinic in San Francisco. We surveyed 77 patients and 26 providers and conducted separate focus groups of older patients living with HIV (n = 31) and staff (n = 20). Transcripts were analyzed using thematic analysis. Themes for a care program were additionally explored using findings from the literature on HIV and aging. Findings: Themes from surveys and focus groups emphasized (a) the need for knowledge expertise in HIV and aging, (b) focus on medical conditions and determinants of health of particular import (e.g. marginal housing) among older PLWH, (c) co-locating specialty services (e.g. cardiology, geriatrics) with primary care, and (d) addressing social isolation. Findings informed the design of a comprehensive, multidisciplinary care model for PLWH called the Golden Compass program composed of four “points”: Heart and Mind (North), Bones and Strength (East), Network and Navigation (South), and Dental, Hearing, and Vision (West). Conclusion: Based on patient and clinic staff perspectives from surveys and focus groups, we designed a multidisciplinary program of integrated primary and specialty care, as well as housing and social support, to address the needs of older PLWH within a safety-net infrastructure. Golden Compass launched in 2017 for PLWH older than 50 years. Future research to evaluate the effectiveness of this care program in improving patient outcomes and satisfaction is ongoing. [ABSTRACT FROM AUTHOR]

Objective: HIV-positive children, adolescents, and young adults are at increased risk poor musculoskeletal outcomes. Increased incidence of vitamin D deficiency in youth living with HIV may further adversely affect musculoskeletal health. We investigated the impact of vitamin D supplementation on a range of musculoskeletal outcomes among individuals aged 0–25 years living with HIV. Methods: A systematic review was conducted using databases: PubMed/Medline, CINAHL, Web of Knowledge, and EMBASE. Interventional randomised control trials, quasi-experimental trials, and previous systematic reviews/meta-analyses were included. Outcomes included: BMD, BMC, fracture incidence, muscle strength, linear growth (height-for-age Z-score [HAZ]), and biochemical/endocrine biomarkers including bone turnover markers. Results: Of 497 records, 20 studies met inclusion criteria. Thirteen studies were conducted in North America, one in Asia, two in Europe, and four in Sub-Saharan Africa. High-dose vitamin D supplementation regimens (1,000–7,000 IU/day) were successful in achieving serum 25-hydroxyvitamin-D (25OHD) concentrations above study-defined thresholds. No improvements were observed in BMD, BMC, or in muscle power, force and strength; however, improvements in neuromuscular motor skills were demonstrated. HAZ was unaffected by low-dose (200–400 IU/day) supplementation. A single study found positive effects on HAZ with high-dose supplementation (7,000 vs 4,000IU/day). Conclusions: Measured bone outcomes were unaffected by high-dose vitamin D supplementation, even when target 25OHD measurements were achieved. This may be due to: insufficient sample size, follow-up, intermittent dosing, non-standardised definitions of vitamin D deficiency, or heterogeneity of enrolment criteria pertaining to baseline vitamin D concentration. High-dose vitamin D may improve HAZ and neuromuscular motor skills. Adequately powered trials are needed in settings where HIV burden is greatest. PROSPERO Number: CRD42016042938. [ABSTRACT FROM AUTHOR]

As HIV-infected adults on successful antiretroviral therapy (ART) are expected to have close to normal lifespans, they will increasingly develop age-related comorbidities. The objective of this cross-sectional study was to compare in the French Dat’AIDS cohort, the HIV geriatric population, aged 75 years and over, to the elderly one, aged from 50 to 74 years. As of Dec 2015, 16,436 subjects (43.8% of the French Dat’AIDS cohort) were aged from 50 to 74 (elderly group) and 572 subjects (1.5%) were aged 75 and over (geriatric group). Durations of HIV infection and of ART were slightly but significantly different, median at 19 and 18 years, and 15 and 16 years in the elderly and geriatric group, respectively. The geriatric group was more frequently at CDC stage C and had a lower nadir CD4. This group had been more exposed to first generation protease inhibitors and thymidine analogues. Despite similar virologic suppression, type of ART at the last visit significantly differed between the 2 groups: triple ART in 74% versus 68.2%, ART ≥ 4 drugs in 4.7% versus 2.7%; dual therapy in 11.6% versus 16.4% in the elderly group and the geriatric group, respectively. In the geriatric group all co-morbidities were significantly more frequent, except dyslipidemia, 4.3% of the elderly group had ≥4 co-morbidities versus18.4% in the geriatric group. Despite more co-morbidities and more advanced HIV infection the geriatric population achieve similar high rate of virologic suppression than the elderly population. A multidisciplinary approach should be developed to face the incoming challenge of aging HIV population. [ABSTRACT FROM AUTHOR]

HIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts <350 cells/μL, PI:C ratios were lower than in HIV- controls (p<0.01), suggesting a reduction in intrinsic beta cell stress among this group. By contrast, HIV+ participants on ART had higher fasting glucose (p<0.0001) and lower HOMA%B (p<0.001) compared to HIV- controls. Among the entire HIV+ population, higher HIV RNA correlated with lower fasting glucose (r = -0.57, p<0.001), higher HOMA%B (r = 0.40, p = 0.001), and lower PI:C ratios (r = -0.42, p<0.001), whereas higher CD4 counts correlated with higher PI:C ratios (r = 0.2, p = 0.00499). Our results suggest that HIV seropositivity in the absence of ART does not worsen beta cell function or glucose homeostasis, but immune reconstitution with ART may be associated with worsened beta cell function. [ABSTRACT FROM AUTHOR]

Objectives: Several studies have involved antiretroviral therapy in the pathogenesis of low bone mineral density (BMD), while others have not confirmed this association. In this study we analyze the impact of HIV status, traditional risk factors and antiretroviral therapy in BMD in an HIV-infected population living in Madrid. Material and methods: We performed a cross-sectional analysis of 107 individuals infected with HIV and exposed to antiretroviral treatment to estimate the prevalence of decreased BMD. Bone mineral density of lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. In a multivariate analysis variables related with HIV status, antiretroviral drugs and traditional risk factors were included. Results: Low BMD was diagnosed in 63 participants (58.9%), including osteoporosis in 11 (10%). At least one cause of osteoporosis was identified in 43 patients (40%), with a deficiency of vitamin D in 86 (89%) and secondary hyperparathyroidism in 30 (28%). In multivariate analysis, increasing age, a treatment based on boosted PI and tenofovir DF, and previous exposure to tenofovir were identified as independent risk factors for a decreased BMD in both lumbar spine and femoral neck. Conclusions: We have confirmed a high prevalence of reduced BMD, which is favoured by ritonavir-boosted PI and TDF. Bone safety should continue to be evaluated in clinical trials and cohort studies in order to demonstrate that the new drugs offer additional advantages regarding the impact on BMD. [ABSTRACT FROM AUTHOR]

Objective: The objective was to develop a multivariable prognostic index for overall mortality over a five-year span integrating classical HIV biomarkers and comorbidities in people living with HIV (PLHIV) aged 60 or older. Design: Prospective multicenter cohort study from the French Dat’AIDS cohort. Methods: All HIV-1 infected patients aged 60 years or older on 1st January 2008 were included. Sociodemographic data, CD4 cell count, CD4 nadir, HIV viral load, history of comorbidities, hepatitis co-infections and laboratory parameters at baseline were considered as potential prognostic variables. Primary outcome was all-cause mortality. Results: Among 1415 patients included, we derived a score comprising the following predictors: Age (65–74: 1 point; ≥75: 8 points), CD4 cell count (200–349: 3 points; <200: 6 points), non-HIV related cancer (6 points), cardiovascular disease (8 points), estimated glomerular filtration rate (30–59 mL/min/1.73m2: 5 points; <30mL/min/1.73m2: 16 points), cirrhosis (13 points), low body mass index (<18.5 kg/m2, 10 points), anemia (6 points). Mean observed score was 7.0 ± 8.0 and ranged from 0 to 45. Score categories defined 4 risk groups for mortality: low, moderate, high and very high risk (5-year survival probability 0.95 (95%CI[0.93–0.97]), 0.90 (95%CI[0.87–0.92]), 0.77 (95%CI[0.68–0.84]) and 0.54 (95%CI[0.43–0.63]) respectively). The score showed good discrimination (C-statistic = 0.76) and calibration. Conclusions: We propose a multivariable prognostic score for mortality among PLHIV aged 60 or over, who will become the predominant population in future years in western populations. It could be a useful tool for research, for developing preventive and treatment strategies according to risk group, and for risk assessment by clinicians. [ABSTRACT FROM AUTHOR]

Antiretroviral therapy (ART) for HIV is vulnerable to unplanned treatment interruptions–consecutively missed doses over a series of days–which can result in virologic rebound. Yet clinicians lack a simple, valid method for estimating the risk of interruptions. If the likelihood of ART interruption could be derived from a convenient-to-gather summary measure of medication adherence, it might be a valuable tool for both clinical decision-making and research. We constructed an a priori probability model of ART interruption based on average adherence and tested its predictions using data collected on 185 HIV-infected, treatment-naïve individuals over the first 90 days of ART in a prospective cohort study in Mbarara, Uganda. The outcome of interest was the presence or absence of a treatment gap, defined as >72 hours without a dose. Using the pre-determined value of 0.50 probability as the cut point for predicting an interruption, the classification accuracy of the model was 73% (95% CI = 66%– 79%), the specificity was 87% (95% CI = 79%– 93%), and the sensitivity was 59% (95% CI = 48%– 69%). Overall model performance was satisfactory, with an area under the receiver operator characteristic curve (AUROC) of 0.85 (95% CI = 0.80–0.91) and Brier score of 0.20. The study serves as proof-of-concept that the probability model can accurately differentiate patients on the continuum of risk for short-term ART interruptions using a summary measure of adherence. The model may also aid in the design of targeted interventions. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) has a reported greater prevalence and poorer treatment outcomes in people living with HIV (PLWH) than comparable HIV-uninfected cohorts. We conducted a cross-sectional study to delineate the factors driving T2D in PLWH in an ethnically diverse cohort, and additionally observed how these have changed over time. Setting: We studied a diverse HIV cohort in London to determine the prevalence and risk factors for T2D, and compared them to a cohort studied 10 years previously. Methods: Patients were classified as normoglycaemic (fasting glucose <6.0 mmol/l) or dysglycaemic (≥6.0 mmol/l). The relative contribution to dysglycaemia of modifiable and fixed factors, including demographics, anthropometrics, comorbidities, immune status, and HIV therapy, were analysed using univariate and logistic regression analyses. Results: T2D prevalence was 15.1% in 2015 with a relative risk of 2.4 compared to the general population. The prevalence compared to 6.8% ten years earlier. The 2015 versus the 2005 cohort was significantly older (median age 49 (42–57) years versus 41 (IQR 35–47), p<0.001), had a higher BMI (27.4 (23.3–29.9) versus 24.9 (22.4–28.0) kg/m2 respectively, p = 0.019) and hypertensive (37.9% versus 19.6 respectively, p<0.001). The strongest predictors of dysglycaemia in the 2015 cohort were hepatic steatosis and hypertension, odds ratios (OR) and 95% confidence intervals (CI) 6.74 (3.48–13.03) and 2.92 (1.66–5.16) respectively, and also HIV-related factors of weight gain following antiretroviral initiation and longer known duration of HIV infection (OR 1.07 (1.04–1.11) and 1.06 (1.02–1.10) respectively). Conclusions: The alarmingly high prevalence of T2D in HIV requires improved screening, targeted to older patients and those with a longer duration of exposure to antiretrovirals. Effective diabetes prevention and management strategies are needed urgently to reduce this risk; such interventions should target both conventional risk factors, such as abdominal obesity, and HIV-specific risk factors such as weight gain following initiation of antiretrovirals. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies indicate that human immunodeficiency virus (HIV)-infection and combination antiretroviral therapy (cART) can affect bone turnover. Furthermore, HIV-infected patients have lower bone mineral density (BMD) compared to a healthy reference population. Objective: To evaluate the longitudinal effect of HIV-infection and cART on bone turnover markers (BTMs) and BMD in men with primary HIV-infection (PHI). Design, methods: Thirty-five PHI-men were divided into two groups, those that received cART for the first time (n = 26) versus no-cART (n = 9). Dual-energy X-ray absorptiometry (DXA) was performed on femoral neck (FN), total hip (TH) and lumbar spine (LS) and BTMs (P1NP, alkaline phosphatase, osteocalcin, ICTP and CTX) were measured at baseline and follow-up. Results: At baseline, the median CD4+ T-cell count was 455 cells/mm3 (IQR 320–620) and plasma viral load 5.4 log10 copies/mL (IQR 4.7–6.0) in the cART treated group, compared to 630 (IQR 590–910) and 4.8 (IQR 4.2–5.1) in the untreated group. The median follow-up time was 60.7 weeks (IQR 24.7–96.0). All BTMs, except ICTP, showed a significant increase during cART versus no changes of BTMs in the untreated group. FN and TH BMD showed a significant decrease in both groups. LS BMD did not change in both groups. Conclusion: Bone turnover increased in PHI-men treated with cART which was accompanied by a decrease in FN and TH BMD. No increase of bone turnover was seen in untreated PHI-men. Our study suggests that cART results in increased bone turnover and decreased BMD of the hip in PHI-men. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the host response to dendritic cell-based immunotherapy and subsequent combined antiretroviral therapy (cART) interruption in HIV-1-infected individuals at the plasma protein level. Design: An autologous dendritic cell (DC) therapeutic vaccine was administered to HIV-infected individuals, stable on cART. The effect of vaccination was evaluated at the plasma protein level during the period preceding cART interruption, during analytical therapy interruption and at viral reactivation. Healthy controls and post-exposure prophylactically treated healthy individuals were included as controls. Methods: Plasma marker (‘analyte’) levels including cytokines, chemokines, growth factors, and hormones were measured in trial participants and control plasma samples using a multiplex immunoassay. Analyte levels were analysed using principle component analysis, cluster analysis and limma. Blood neutrophil counts were analysed using linear regression. Results: Plasma analyte levels of HIV-infected individuals are markedly different from those of healthy controls and HIV-negative individuals receiving post-exposure prophylaxis. Viral reactivation following cART interruption also affects multiple analytes, but cART interruption itself only has only a minor effect. We find that Thyroxine-Binding Globulin (TBG) levels and late-stage neutrophil numbers correlate with the time off cART after DC vaccination. Furthermore, analysis shows that cART alters several regulators of blood glucose levels, including C-peptide, chromogranin-A and leptin. HIV reactivation is associated with the upregulation of CXCR3 ligands. Conclusions: Chronic HIV infection leads to a change in multiple plasma analyte levels, as does virus reactivation after cART interruption. Furthermore, we find evidence for the involvement of TBG and neutrophils in the response to DC-vaccination in the setting of HIV-infection. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is a major comorbidity among HIV-infected individuals. Common carotid artery intima-media thickness (cCIMT) is a valid and reliable subclinical measure of atherosclerosis and is known to predict CVD. We performed genome-wide association (GWA) and admixture analysis among 682 HIV-positive and 288 HIV-negative Black, non-Hispanic women from the Women’s Interagency HIV study (WIHS) cohort using a combined and stratified analysis approach. We found some suggestive associations but none of the SNPs reached genome-wide statistical significance in our GWAS analysis. The top GWAS SNPs were rs2280828 in the region intergenic to mediator complex subunit 30 and exostosin glycosyltransferase 1 (MED30 | EXT1) among all women, rs2907092 in the catenin delta 2 (CTNND2) gene among HIV-positive women, and rs7529733 in the region intergenic to family with sequence similarity 5, member C and regulator of G-protein signaling 18 (FAM5C | RGS18) genes among HIV-negative women. The most significant local European ancestry associations were in the region intergenic to the zinc finger and SCAN domain containing 5D gene and NADH: ubiquinone oxidoreductase complex assembly factor 1 (ZSCAN5D | NDUF1) pseudogene on chromosome 19 among all women, in the region intergenic to vomeronasal 1 receptor 6 pseudogene and zinc finger protein 845 (VN1R6P | ZNF845) gene on chromosome 19 among HIV-positive women, and in the region intergenic to the SEC23-interacting protein and phosphatidic acid phosphatase type 2 domain containing 1A (SEC23IP | PPAPDC1A) genes located on chromosome 10 among HIV-negative women. A number of previously identified SNP associations with cCIMT were also observed and included rs2572204 in the ryanodine receptor 3 (RYR3) and an admixture region in the secretion-regulating guanine nucleotide exchange factor (SERGEF) gene. We report several SNPs and gene regions in the GWAS and admixture analysis, some of which are common across HIV-positive and HIV-negative women as demonstrated using meta-analysis, and also across the two analytic approaches (i.e., GWA and admixture). These findings suggest that local European ancestry plays an important role in genetic associations of cCIMT among black women from WIHS along with other environmental factors that are related to CVD and may also be triggered by HIV. These findings warrant confirmation in independent samples. [ABSTRACT FROM AUTHOR]

Background: People aging with HIV show variable health trajectories. Our objective was to identify longitudinal predictors of frailty severity and mortality among a group aging with HIV. Methods: Exploratory analyses employing a multistate transition model, with data from the prospective Modena HIV Metabolic Clinic Cohort Study, based in Northern Italy, begun in 2004. Participants were followed over four years from their first available visit. We included all 963 participants (mean age 46.8±7.1; 29% female; 89% undetectable HIV viral load; median current CD4 count 549, IQR 405–720; nadir CD4 count 180, 81–280) with four-year data. Frailty was quantified using a 31-item frailty index. Outcomes were frailty index score or mortality at four-year follow-up. Candidate predictor variables were baseline frailty index score, demographic (age, sex), HIV-disease related (undetectable HIV viral load, current CD4+ T-cell count, nadir CD4 count, duration of HIV infection, and duration of antiretroviral therapy [ARV] exposure), and behavioral factors (smoking, injection drug use (IDU), and hepatitis C virus co-infection). Results: Four-year mortality was 3.0% (n = 29). In multivariable analyses, independent predictors of frailty index at follow-up were baseline frailty index (RR 1.06, 95% CI 1.05–1.07), female sex (RR 0.93, 95% CI 0.87–0.98), nadir CD4 cell count (RR 0.96, 95% CI 0.93–0.99), duration of HIV infection (RR 1.06, 95% CI 1.01–1.12), duration of ARV exposure (RR 1.08, 95% CI 1.02–1.14), and smoking pack-years (1.03, 1.01–1.05). Independent predictors of mortality were baseline frailty index (OR 1.19, 1.02–1.38), current CD4 count (0.34, 0.20–0.60), and IDU (2.89, 1.30–6.42). Conclusions: Demographic, HIV-disease related, and social and behavioral factors appear to confer risk for changes in frailty severity and mortality among people aging with HIV. [ABSTRACT FROM AUTHOR]

In Australia, almost half of HIV-positive people are now aged over 50 and are predominately gay and bisexual men (GBM). Compared to the general HIV-negative population, GBM engage more in behaviours that may increase the risk of age-related comorbidities, including smoking, high alcohol consumption and recreational drug use. The objective of APPLES was to compare comorbidities and risk factors in HIV-positive older GBM with an appropriate control group of HIV-negative GBM. We undertook a prospectively recruited cross-sectional sample of HIV-positive and HIV-negative GBM ≥ 55 years. Detailed data collection included clinic data, a health and lifestyle survey, and blood sample collection. We report key demographic, laboratory markers and self-reported comorbidities by HIV status. For selected comorbidities we also adjust HIV status a priori for age, smoking and body mass index. Over 16 months 228 HIV-positive and 218 HIV-negative men were recruited. Median age was 63 years (IQR: 59–67). Although more HIV-positive men reported having ever smoked, smoking status was not statistically different between HIV positive and HIV negative men (p = 0.081). Greater alcohol use was reported by HIV-negative men (p = 0.002), and recreational drug use reported more often by HIV-positive men (p<0.001). After adjustment, HIV-positive men had significantly increased odds of diabetes (adjusted Odds ratio (aOR): 1.97, p = 0.038), thrombosis (aOR: 3.08, p = 0.007), neuropathy (aOR: 34.6, P<0.001), and non-significantly increased odds for heart-disease (aOR: 1.71, p = 0.077). In conclusion, HIV-positive GBM have significantly increased odds for key self-reported comorbidities. This study underscores the importance of an appropriate HIV-negative control group for more accurate evaluation of the risk and attribution of age-related comorbidities in HIV-positive people. [ABSTRACT FROM AUTHOR]

Background: HIV-infected patients have an increased risk of cardiovascular disease (CVD). Impaired endothelial function is an early risk factor for CVD in the general population. It is presumed that HIV infection is associated with impaired endothelial function, but results have been inconsistent. Objectives: Our objectives were to determine the relationships between HIV infection, virologic suppression with antiretroviral therapy (ART), in vivo measures of conduit artery and microvascular endothelial function, and circulating biomarkers of pathways associated with CVD. Methods: We performed a cross-sectional analysis of three prospectively enrolled groups from a single center: 28 were HIV-infected and virologically-suppressed on a regimen of FTC/TDF/EFV (HIV+ART+), 44 were HIV-infected but not on ART (HIV+ART-), and 39 were HIV-uninfected healthy volunteers (HIV-) matched to the HIV+ART- group for age, sex, smoking status, and height. None had diabetes, uncontrolled hypertension, known CVD, or other pro-inflammatory condition. Flow mediated dilation (FMD), nitroglycerin-mediated dilation (NTGMD), reactive hyperemia velocity time integral (RHVTI), and FMD/RHVTI of the brachial artery were measured, as well as circulating biomarkers of systemic inflammation, metabolism, oxidative stress, and endothelial activation. Results: No significant differences were found amongst the three groups in FMD (P = 0.46), NTGMD (P = 0.42), RHVTI (P = 0.17), and FMD/RHVTI (P = 0.22) in unadjusted comparisons. Adjusted ANOVA models which included brachial artery diameter, demographics, and conventional CVD risk factors did not appreciably change these findings. In pairwise comparisons, the HIV+ART- group had significantly higher soluble tumor necrosis factor receptor II, soluble CD163, β-2 microglobulin, interferon-γ- induced protein-10, tissue inhibitor of metalloproteinase-1, and vascular cell adhesion molecule-1 compared to the other two groups (all p<0.05). Correlates of endothelial function differed between study groups. Conclusion: Although untreated HIV infection was associated with elevated levels of several biomarkers of inflammation and endothelial activation, we were unable to demonstrate differences in measures of conduit artery and microvascular endothelial function in this study population. [ABSTRACT FROM AUTHOR]

Rationale: Individuals with HIV are at increased risk for coronary artery disease (CAD). Early detection of subclinical CAD by assessment of coronary artery calcium (CAC) may help risk stratify and prevent CAD events in these individuals. However, the current standard to quantify CAC i.e. Agatston scoring requires EKG-gated cardiac CT imaging. Objective: To determine if the assessment of CAC using non-EKG-gated chest CT and the Weston scoring system is a useful surrogate for Agatston scores in HIV-infected and HIV-uninfected individuals. Methods and measurements: CAC was assessed by both the Weston and Agatston score in 108 men enrolled in the Multicenter AIDS Cohort Study. Results: Participants were 55.2 (IQR 50.4; 59.9) years old and 62 (57.4%) were seropositive for HIV. Inter-observer agreement (rs = 0.94, κ = 90.0%, p<0.001, n = 21) and intra-observer agreement (rs = 0.95, κ = 95.2%, p<0.001, n = 97) for category of Weston score were excellent. Weston scores were associated with similar CAD risk factors as Agatston scores (age, race, HDL cholesterol level, all p<0.05) in our cohort. There was excellent correlation (rs = 0.92, p<0.001) and agreement (κw = 0.77, p<0.001) between Weston and Agatston scores. Conclusions: This study is the first to examine calcium scoring using chest CT in HIV-infected individuals and to independently validate the Weston score as a surrogate for the Agatston score. In clinical or research settings where EKG-gated cardiac CT is not feasible for the assessment of coronary calcium, Weston scoring by using chest CT should be considered. [ABSTRACT FROM AUTHOR]

Objective: To describe trends in the prevalence of diabetes among hospitalized HIV-infected patients between 1997 and 2012 in Spain and compare them with those of age- and sex-matched non–HIV-infected patients. Methods: The study was based on Spanish national hospital discharge data. We performed a retrospective study for the period 1997–2012. HIV infection (HIV-infected versus non–HIV-infected [control group])and calendar period in relation to widespread use of combination antiretroviral therapy (cART) (1997–1999; 2000–2003; 2004–2007 and 2008–2012), were the exposure variables The outcome variables were diagnosis of diabetes and in-hospital mortality (IHM). Results: From 1997 to 2012, we identified 91,752 cases of diabetes: 15,398 in the HIV-infected group (403,277 hospital admissions) and 76,354 in the non–HIV-infected group (1,503,467 hospital admissions). Overall, HIV-infected patients had lower prevalence values for diabetes than non–HIV-infected patients throughout the follow-up (3.8% vs. 5.1%; p<0.001). The prevalence of diabetes increased 1.56-fold among non–HIV-infected patients and 4.2-fold among HIV-infected patients. The prevalence of diabetes in females was almost twice as high in HIV-infected patients as in non–HIV-infected patients during the last study period (4.72% vs. 2.88%; p<0.001). Diabetes showed a protective effect against IHM throughout the study period (aOR = 0.70; 95%CI, 0.65–0.75). Conclusions: During the cART era, the prevalence of diabetes has increased sharply among HIV-infected hospitalized patients compared with matched non–HIV-infected subjects. The prevalence of diabetes is rising very fast among HIV-infected women. Diabetes has a protective effect on IHM among HIV-infected patients. Nevertheless, our study has several limitations. No information is available in the database used on important sociodemographic characteristics and relevant clinical variables including duration of the HIV infection, treatments used, drug resistance, treatment adherence or CD4 count, among others. Also, it is possible that increase of diabetes prevalence could reflect the improvement in recording habits. [ABSTRACT FROM AUTHOR]

Background: High BMI and blood pressure are leading chronic disease risk factors in South Africa. Longterm effects of HIV and ART on adiposity and blood pressure are poorly understood, and direct comparisons of risk factor trajectories in HIV- versus HIV+ populations are rare. Methods: In 2003 and 2010, height, weight, and blood pressure were recorded in a study population (n = 505) in KwaZulu-Natal, South Africa (30% adult HIV prevalence). We modeled change in BMI and BP longitudinally in HIV- individuals (n = 315), seroconverters (n = 32), HIV+ patients not on ART (HIV+ART−; n = 52), HIV+ patients on ART for 0–<2 years as of 2010 (HIV+ART0–<2 yrs; n = 18), patients on ART for 2–5 years (HIV+ART2–5yrs; n = 44), and a subgroup with unknown HIV status (n = 44). Difference-in-differences were assessed in reference to the HIV- population. Results: Between 2003 and 2010, BMI increased significantly in the HIV- group, by 0.874 (95% CI 0.339, 1.41; p = 0.001), to 30.4. BMI drop was significantly greater in HIV+ART0-<2yrs than in HIV+ART2–5yrs (p = 0.005). DID in BMI in HIV+ART0-<2yrs versus the reference was -5.21 (95% CI -7.53, -2.90; p = 0.001), and DID in HIV+ART2–5yrs versus reference was -1.35 (95% CI -2.89, 0.189; p = 0.086). DID in SBP in HIV+ART−vs HIV- DID was -7.55 mmHg (95% CI -13.2 to -1.90; p = 0.009). Conclusion: Short-term ART (0–<2 years) was associated with larger weight loss than either no ART or long-term ART. Once on ART for 2+ years, individuals ‘caught up’ on weight gain with the HIV- population. Our results showcase the importance of health system readiness to address the burgeoning double burden of disease in South Africa. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) is a leading health threat for HIV+ patients on antiretroviral therapy (ART); cardiometabolic comorbidities are key predictors of risk. Data are limited on incidence of metabolic comorbidities in HIV+ individuals initiating ART in low and middle income countries (LMICs), particularly for Hispanics. We examined incidence of diabetes and obesity in a prospective cohort of those initiating ART in the Dominican Republic. Methods: Participants ≥18 years, initiating ART <90 days prior to study enrollment, were examined for incidence of impaired fasting glucose (IFG), diabetes mellitus (DM), overweight, and obesity. Fasting plasma glucose (FPG) 100-125mg/dl defined IFG; FPG ≥126 mg/dl, diagnosis per medical record, or use of hypoglycemic medication defined DM. Overweight and obesity were BMI 25–30 and ≥30kg/m2, respectively. Dyslipidemia was total cholesterol ≥240mg/dl or use of lipid-lowering medication. Framingham risk equation was used to determine ten-year CVD risk at the end of observation. Results: Of 153 initiating ART, 8 (6%) had DM and 23 (16%) had IFG at baseline, 6 developed DM (28/1000 person-years follow up [PYFU]) and 46 developed IFG (329/1000 PYFU). At baseline, 24 (18%) were obese and 36 (27%) were overweight, 15 became obese (69/1000 PYFU) and 22 became overweight (163/1000 PYFU). Median observation periods for the diabetes and obesity analyses were 23.5 months and 24.3 months, respectively. Increased CVD risk (≥10% 10-year Framingham risk score) was present for 13% of the cohort; 79% of the cohort had ≥1 cardiometabolic comorbidity, 48% had ≥2, and 13% had all three. Conclusions: In this Hispanic cohort in an LMIC, incidences of IFG/DM and overweight/obesity were similar to or higher than that found in high income countries, and cardiometabolic disorders affected three-quarters of those initiating ART. Care models incorporating cardiovascular risk reduction into HIV treatment programs are needed to prevent CVD-associated mortality in this vulnerable population. [ABSTRACT FROM AUTHOR]

We investigate the associations of three established plasma biomarkers in the context of HIV and treatment-related variables including a comprehensive cardiovascular disease risk assessment, within a large ambulatory HIV cohort. Patients were recruited in 2010 to form the Royal Perth Hospital HIV/CVD risk cohort. Plasma sCD14, sCD163 and CXCL10 levels were measured in 475 consecutive patients with documented CVD risk (age, ethnicity, gender, smoking, blood pressure, BMI, fasting metabolic profile) and HIV treatment history including immunological/virological outcomes. The biomarkers assessed showed distinct associations with virological response: CXCL10 strongly correlated with HIV-1 RNA (p<0.001), sCD163 was significantly reduced among ‘aviraemic’ patients only (p = 0.02), while sCD14 was unaffected by virological status under 10,000 copies/mL (p>0.2). Associations between higher sCD163 and protease inhibitor therapy (p = 0.05) and lower sCD14 with integrase inhibitor therapy (p = 0.02) were observed. Levels of sCD163 were also associated with CVD risk factors (age, ethnicity, HDL, BMI), with a favourable influence of Framingham score <10% (p = 0.04). Soluble CD14 levels were higher among smokers (p = 0.002), with no effect of other CVD risk factors, except age (p = 0.045). Our findings confirm CXCL10, sCD163 and sCD14 have distinct associations with different aspects of HIV infection and treatment. Levels of CXCL10 correlated with routinely monitored variables, sCD163 levels reflect a deeper level of virological suppression and influence of CVD risk factors, while sCD14 levels were not associated with routinely monitored variables, with evidence of specific effects of smoking and integrase inhibitor therapy warranting further investigation. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor23 (FGF23), an early marker of kidney dysfunction, is associated with cardiovascular death. Its role in HIV-positive individuals is unknown. We measured FGF23 in 100 HIV-negative and 191 HIV-positive nondiabetic adults with normal baseline estimated glomerular filtration rate (GFR). We measured GFR by iohexol annually, albumin-creatinine ratio (ACR) every 6 months, as well as pulse wave velocity, carotid plaque, and carotid intima media thickness (IMT) at baseline and 2 years. Progressive albuminuria was defined as follow-up ACR ≥2-fold than baseline and ≥30 mg/g. Regression models assessed associations of FGF23 with baseline factors and longitudinal changes in disease markers. FGF23 levels were similar in HIV serostatus. Among HIV-positive persons, factors independently associated with higher baseline FGF23 levels included female (adjusted ratio of geometric means [95% CI],1.46 [1.21,1.76]), serum phosphorus (1.20 [1.03,1.40]), HCV (1.31 [1.10,1.56]) and non-suppressed HIV RNA (1.27 [1.01,1.76]). At baseline, FGF23 was not associated with GFR, albuminuria, carotid plaque, or carotid IMT in cross-sectionally adjusted analysis of HIV-positive individuals. However, higher baseline FGF23 was associated with progressive albuminuria (odds ratio1.48 [95% CI]:1.05,2.08) and a more rapid increase in IMT (13 μm/year, 95% CI,3,24). These findings suggest a role for FGF23 in HIV-positive populations in identifying patients at greater risk for cardiovascular and kidney disease. [ABSTRACT FROM AUTHOR]

HIV-infected patients appear to have a significantly greater risk of non-AIDS comorbidities such as osteoporosis and atherosclerosis. Subjects with osteoporosis are at a higher risk of developing cardiovascular disease than those with normal bone mass, therefore a possible relation between these two conditions can be hypothesized. In the setting of HIV infection, several factors might contribute to bone disease and endothelial dysfunction. The aim of our study was to evaluate the relationship between bone and cardiovascular disease and to investigate the role of traditional factors, T-cell phenotype and osteoprotegerin in HIV positive subjects on effective antiretroviral therapy. We included 94 HIV positive subjects on antiretroviral therapy with virological suppression and 41 healthy subjects matched for age and gender as a control group. Carotid-Intima Media Thickness (c-IMT) and bone mineral density (BMD) were performed by ultrasound and DEXA, respectively. CD4+/CD8+ T-cell activation, senescence and osteoprotegerin plasma levels were measured by flow-cytometry and ELISA, respectively. Among HIV positive patients, 56.4% had osteopenia/osteoporosis and 45.7% had pathological c-IMT (>0.9mm). Subjects with pathological c-IMT and BMD exhibited higher CD4+ and CD8+ activated, CD8+ senescent and osteoprotegerin than subjects with normal c-IMT and BMD. HIV positive subjects with osteopenia/osteoporosis had higher c-IMT than subjects with normal BMD, and linear regression analysis showed a negative correlation between BMD and c-IMT. Several factors are implicated in the pathogenesis of non-AIDS comorbidities in HIV positive patients. Osteoprotegerin together with inflammation and immunosenescence in HIV positive patients could affect bone and vascular system and could be considered as a possible common link between these two diseases. [ABSTRACT FROM AUTHOR]

Introduction: Abnormal diurnal blood pressure (BP) rhythms may contribute to the high cardiovascular disease risk in HIV-positive (HIV+) individuals. To synthesize the current literature on ambulatory BP monitoring (ABPM) in HIV+ individuals, a systematic literature review and meta-analysis were performed. Methods: Medical databases were searched through November 11, 2015 for studies that reported ABPM results in HIV+ individuals. Data were extracted by 2 reviewers and pooled differences between HIV+ and HIV-negative (HIV-) individuals in clinic BP and ABPM measures were calculated using random-effects inverse variance weighted models. Results: Of 597 abstracts reviewed, 8 studies with HIV+ cohorts met the inclusion criteria. The 420 HIV+ and 714 HIV- individuals in 7 studies with HIV- comparison groups were pooled for analyses. The pooled absolute nocturnal systolic and diastolic BP declines were 3.16% (95% confidence interval [CI]: 1.13%, 5.20%) and 2.92% (95% CI: 1.64%, 4.19%) less, respectively, in HIV+ versus HIV- individuals. The pooled odds ratio for non-dipping systolic BP (nocturnal systolic BP decline <10%) in HIV+ versus HIV- individuals was 2.72 (95% CI: 1.92, 3.85). Differences in mean clinic, 24-hour, daytime, or nighttime BP were not statistically significant. I2 and heterogeneity chi-squared statistics indicated the presence of high heterogeneity for all outcomes except percent DBP dipping and non-dipping SBP pattern. Conclusions: An abnormal diurnal BP pattern may be more common among HIV+ versus HIV- individuals. However, results were heterogeneous for most BP measures, suggesting more research in this area is needed. [ABSTRACT FROM AUTHOR]

Objective: We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection. Methods: A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations. Results: Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels. Conclusions: The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here provide valuable insights into the effectiveness and tolerability of dual therapy regimens, it remains unclear whether these potential benefits can be maintained long-term. Appropriately powered studies with longer follow-up periods are needed to more definitively assess potential toxicity reduction advantages with dual therapy. [ABSTRACT FROM AUTHOR]

Background: NRTI-sparing regimens may avoid long-term mitochondrial, bone and renal toxicities and maintain viral suppression. Methods: In the RADAR study, 85 antiretroviral-naïve HIV-infected patients were randomized to receive either raltegravir (RAL) (n = 42) or tenofovir/emtricitabine (TDF/FTC) (n = 43), each with ritonavir-boosted darunavir (DRV/r). Virologic efficacy was assessed at weeks 24 and 48. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) scan at baseline and week 48, and bone turnover markers (BTM) assessed at weeks 0, 16 and 48. Results: Using an intention-to-treat analysis, 62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175). Premature treatment discontinuation was the main cause for failure. No treatment-emergent resistance was observed. Changes from baseline in RAL vs. TDF/FTC for CD4+ (+199 vs. +216 cells/µL, p = 0.63), total cholesterol/HDL (−0.25 vs. −0.71 mg/dL (p = 0.270), and eGFR (−4.4 vs. −7.9 ml/min, p = 0.44) were comparable between groups. Changes in subtotal BMD to week 48 were: +9.2 with RAL vs. −7 g/cm2 with TDF/FTC (p = 0.002). Mean CTX changes were +0.04 vs. +0.24 ng/mL (p = 0.001), and mean P1NP changes were +3.59 vs. +30.09 ng/mL (p = 0.023). BTM changes at week 16 predicted change in BMD by week 48 (R = −0.394, p = 0.003 for CTX; and R = −0.477, p<0.001 for P1NP). Conclusion: The NRTI-sparing regimen RAL+DRV/r did not achieve similar week 48 virologic efficacy compared with TDF/FTC+DRV/r, but was better with regard to markers of bone health. Trial Registration: ClinicalTrials.gov NCT 00677300 [ABSTRACT FROM AUTHOR]

Study Objectives: We investigated the association of HIV infection and highly active antiretroviral therapy (HAART) with sleep disordered breathing (SDB), fatigue, and sleepiness. Methods: HIV-uninfected men (HIV−; n = 60), HIV-infected men using HAART (HIV+/HAART+; n = 58), and HIV-infected men not using HAART (HIV+/HAART−; n = 41) recruited from two sites of the Multicenter AIDS cohort study (MACS) underwent a nocturnal sleep study, anthropometric assessment, and questionnaires for fatigue and the Epworth Sleepiness Scale. The prevalence of SDB in HIV- men was compared to that in men matched from the Sleep Heart Health Study (SHHS). Results: The prevalence of SDB was unexpectedly high in all groups: 86.7% for HIV−, 70.7% for HIV+/HAART+, and 73.2% for HIV+/HAART−, despite lower body-mass indices (BMI) in HIV+ groups. The higher prevalence in the HIV− men was significant in univariate analyses but not after adjustment for BMI and other variables. SDB was significantly more common in HIV− men in this study than those in SHHS, and was common in participants with BMIs <25 kg/m2. HIV+ men reported fatigue more frequently than HIV− men (25.5% vs. 6.7%; p = 0.003), but self-reported sleepiness did not differ among the three groups. Sleepiness, but not fatigue, was significantly associated with SDB. Conclusions: SDB was highly prevalent in HIV− and HIV+ men, despite a normal or slightly elevated BMI. The high rate of SDB in men who have sex with men deserves further investigation. Sleepiness, but not fatigue, was related to the presence of SDB. Clinicians caring for HIV-infected patients should distinguish between fatigue and sleepiness when considering those at risk for SDB, especially in non-obese men. [ABSTRACT FROM AUTHOR]

Introduction: Vitamin D deficiency is highly prevalent and is associated with bone disease, cardiovascular disease, metabolic syndrome and malignancy. Injection drug users (IDUs), with or without HIV infection, are at risk for these conditions; however, limited data on vitamin D deficiency exist in this population. We determined the prevalence and correlates of vitamin D deficiency among urban IDUs in the AIDS Linked to the IntraVenous Experience (ALIVE) Study cohort. Methods: For this cross-sectional sub-study, vitamin D deficiency was defined as a serum 25(OH)-vitamin D level <20 ng/mL. Multivariable logistic regression was used to identify factors independently associated with vitamin D deficiency. Results: Of 950 individuals analyzed, 29% were HIV-infected. The median age was 49 years; 65% were male, and 91% were black. The median vitamin D level was 13.5 ng/mL (IQR, 9.0–20.3); 74% were deficient (68% in HIV-infected vs. 76% in HIV-uninfected, p = 0.01). Non-black race, fall/winter season, multivitamin intake, higher serum albumin, HCV seropositivity and HIV-infection were associated with significantly lower odds of vitamin D deficiency. Conclusions: Vitamin D deficiency is prevalent among IDUs. Notably, HIV-infected IDUs were less likely to be vitamin D deficient. Higher vitamin D levels were associated with multivitamin intake and with higher albumin levels, suggesting that nutritional status contributes substantially to deficiency. The association between HCV serostatus and vitamin D level remains unclear. Further investigation is needed to define the clinical implications of the heavy burden of vitamin D deficiency in this high-risk, aging population with significant co-morbidities. [ABSTRACT FROM AUTHOR]

Study Background: Vitamin D has wide-ranging effects on the immune system, and studies suggest that low serum vitamin D levels are associated with worse clinical outcomes in HIV. Recent studies have identified an interaction between antiretrovirals used to treat HIV and reduced serum vitamin D levels, but these studies have been done in North American and European populations. Methods: Using a prospective cohort study design nested in a multinational clinical trial, we examined the effect of three combination antiretroviral (cART) regimens on serum vitamin D levels in 270 cART-naïve, HIV-infected adults in nine diverse countries, (Brazil, Haiti, Peru, Thailand, India, Malawi, South Africa, Zimbabwe and the United States). We evaluated the change between baseline serum vitamin D levels and vitamin D levels 24 and 48 weeks after cART initiation. Results: Serum vitamin D levels decreased significantly from baseline to 24 weeks among those randomized to efavirenz/lamivudine/zidovudine (mean change: −7.94 [95% Confidence Interval (CI) −10.42, −5.54] ng/ml) and efavirenz/emtricitabine/tenofovir-DF (mean change: −6.66 [95% CI −9.40, −3.92] ng/ml) when compared to those randomized to atazanavir/emtricitabine/didanosine-EC (mean change: −2.29 [95% CI –4.83, 0.25] ng/ml). Vitamin D levels did not change significantly between week 24 and 48. Other factors that significantly affected serum vitamin D change included country (p<0.001), season (p<0.001) and baseline vitamin D level (p<0.001). Conclusion: Efavirenz-containing cART regimens adversely affected vitamin D levels in patients from economically, geographically and racially diverse resource-limited settings. This effect was most pronounced early after cART initiation. Research is needed to define the role of Vitamin D supplementation in HIV care. [ABSTRACT FROM AUTHOR]

Background: Therapy with tenofovir is associated with lower bone mineral density (BMD), higher markers of bone turnover and increased fracture risk in HIV-infected adults. Bone structural parameters generated by hip structural analysis may represent a separate measure of bone strength, but have not been assessed in HIV. Methods: Dual-energy X-ray absorptiometry (DXA) scans from 254 HIV-infected adults randomised to simplify their existing dual nucleoside analogue reverse transcriptase inhibitor therapy to coformulated tenofovir-emtricitabine or abacavir-lamivudine were analysed using DXA-derived hip structural analysis software. Hip structural parameters included femoral strength index, section modulus, cross-sectional area, and cross-sectional moment of inertia. We used one-way ANOVA to test the relationship between nucleoside analogue type at baseline and structural parameters, multivariable analysis to assess baseline covariates associated with femoral strength index, and t-tests to compare mean change in structural parameters over 96 weeks between randomised groups. Results: Participants taking tenofovir at baseline had lower section modulus (−107.3 mm2, p = 0.001), lower cross-sectional area (−15.01 mm3, p = 0.001), and lower cross-sectional moment of inertia (−2,036.8 mm4, p = 0.007) than those receiving other nucleoside analogues. After adjustment for baseline risk factors, the association remained significant for section modulus (p = 0.008) and cross-sectional area (p = 0.002). Baseline covariates significantly associated with higher femoral strength index were higher spine T-score (p = 0.001), lower body fat mass (p<0.001), lower bone alkaline phosphatase (p = 0.025), and higher osteoprotegerin (p = 0.024). Hip structural parameters did not change significantly over 96 weeks and none was significantly affected by treatment simplification to tenofovir-emtricitabine or abacavir-lamivudine. Conclusion: In this population, tenofovir use was associated with reduced composite indices of bone strength as measured by hip structural analysis, but none of the structural parameters improved significantly over 96 weeks with tenofovir cessation. Trial Registration: ClinicalTrials.gov NCT00192634 [ABSTRACT FROM AUTHOR]