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Study Objectives: We evaluated differences in processes and outcomes of HIV-related pneumonia care among patients in Veterans Affairs (VA), public, and for-profit and not-for-profit private hospitals in the United States. We compared the results of our current study (1995 to 1997) with those of our previous study that included a sample of patients receiving care during the years 1987 to 1990 to determine how HIV-related pneumonia care had evolved over the last decade.Setting/patients: The sample consisted of 1,231 patients with HIV infection who received care for Pneumocystis carinii pneumonia (PCP) and 750 patients with HIV infection who received care for community-acquired pneumonia (CAP) during the years 1995 to 1997.Measurement: We conducted a retrospective medical record review and evaluated patient and hospital characteristics, HIV-related processes of care (timely use of anti-PCP medications, adjunctive corticosteroids), non-HIV-related processes of care (timely use of CAP treatment medications, diagnostic testing, ICU utilization, rates of endotracheal ventilation, placement on respiratory isolation), length of inpatient hospital stay, and inpatient mortality.Results: Rates of timely use of antibiotics and adjunctive corticosteroids for treating PCP were high and improved dramatically from the prior decade. However, compliance with consensus guidelines that recommend < 8 h as the optimal time window for initiation of antibiotics to treat CAP was lower. For both PCP and CAP, variations in processes of care and lengths of in-hospital stays, but not mortality rates, were noted at VA, public, private not-for-profit hospitals, and for-profit hospitals.Conclusions: This study provides the first overview of HIV-related pneumonia care in the early highly active antiretroviral therapy era, and contrasts current findings with those of a similarly conducted study from a decade earlier. Quality of care for patients with PCP improved, but further efforts are needed to facilitate the appropriate management of CAP. In the third decade of the epidemic, it will be important to monitor whether variations in processes of care for various HIV-related clinical diagnoses among different types of hospitals persist. [ABSTRACT FROM AUTHOR]

Background: Optimal timing of antiretroviral therapy (ART) initiation for HIV-infected persons remains unclear.Objective: To assess survival benefit of initiating ART at different CD4+ cell counts.Design: Prospective observational study.Setting: U.S. clinics in the HIV Outpatient Study (HOPS).Patients: HIV-infected patients with CD4+ cell counts, plasma HIV RNA viral load, and ART use recorded from January 1994 through March 2002.Measurements: Before initiation of ART, patients were grouped by their CD4+ cell counts into three subgroups: 0.201 to 0.350 x 10(9) cells/L (n = 399), 0.351 to 0.500 x 10(9) cells/L (n = 327), and 0.501 to 0.750 x 10(9) cells/L (n = 122). We compared mortality rates for each CD4+ subgroup among patients who initiated ART and patients who delayed ART until reaching a lower CD4+ subgroup.Results: Mortality rates for 340 patients who initiated ART and 59 who delayed ART in the CD4+ subgroup of 0.201 to 0.350 x 10(9) cells/L were 15.4 and 56.4 deaths per 1000 person-years, respectively (rate ratio, 0.27 [95% CI, 0.14 to 0.55]; P < 0.001). For the CD4+ subgroup of 0.351 to 0.500 x 10(9) cells/L, mortality rates for 240 patients who initiated ART and 887 who delayed ART were 10.0 and 16.6 deaths per 1000 person-years, respectively (rate ratio, 0.61 [CI, 0.22 to 1.67]; P = 0.17). For the CD4+ subgroup of 0.501 to 0.750 x 10(9) cells/L, mortality rates in 55 patients who initiated ART and 67 who delayed ART were 7.5 and 3.1 deaths per 1000 person-years, respectively (rate ratio, 1.20 [CI, 0.17 to 8.53]; P > 0.2). Patients in the 0.201 to 0.350 x 10(9) cells/L and 0.351 to 0.500 x 10(9) cells/L CD4+ subgroups who initiated ART were more likely than those who delayed ART to achieve an undetectable HIV viral load (P = 0.03 and 0.04, respectively).Conclusions: Among HIV-infected persons with CD4+ cell counts of 0.201 to 0.350 x 10(9) cells/L, initiating ART is associated with reduced mortality compared with delaying such therapy. Survival benefits of earlier ART initiation (at CD4+ cell counts of 0.351 to 0.500 x 10(9) cells/L) are possible. [ABSTRACT FROM AUTHOR]

Background: HIV-positive persons bear an excess burden of chronic kidney disease (CKD); however, conventional methods to assess kidney health are insensitive and non-specific for detecting early kidney injury. Urinary biomarkers can detect early kidney injury, and may help mitigate the risk of overt CKD.Methods: Cross-sectional study of HIV-positive persons in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. We measured levels of 14 biomarkers, capturing multiple dimensions of kidney injury. We then evaluated associations of known CKD risk factors with urine biomarkers using separate multivariable adjusted models for each biomarker.Results: Of the 198 participants, one third were on HAART and virally suppressed. The vast majority (95%) had preserved kidney function as assessed by serum creatinine, with a median eGFR of 103 ml/min/1.73 m2 (interquartile range (IQR): 88, 116). In our multivariable analyses, the associations of each CKD risk factor with urinary biomarker levels varied in magnitude. For example, HIV viral load was predominantly associated with elevations in interleukin(IL)-18, and albuminuria, while higher CD4 levels were associated with lower monocyte chemoattractant protein-1 (MCP-1) and β2-microglobulin. In contrast, older age was significantly associated with elevations in α1-microglobulin, kidney injury marker-1, clusterin, MCP-1, and chitinase-3-like protein-1 levels, as well as lower epidermal growth factor, and uromodulin levels.Conclusions: Among HIV-positive persons, CKD risk factors are associated with unique and heterogeneous patterns of changes in urine biomarkers levels. Additional work is needed to develop parsimonious algorithms that integrate multiple biomarkers and clinical data to discern the risk of overt CKD and its progression. [ABSTRACT FROM AUTHOR]

Background: Pre-diabetes mellitus (DM) is associated with proteinuria, a risk factor for chronic kidney disease. While people with human immunodeficiency virus (HIV; PWH) have a higher risk of proteinuria than people without HIV (PWOH), it is unknown whether incident proteinuria differs by HIV serostatus among prediabetic persons., Methods: The urine protein-to-creatinine ratio was measured at semiannual visits among men in the Multicenter AIDS Cohort Study since April 2006. Men with pre-DM on or after April 2006 and no prevalent proteinuria or use of antidiabetic medications were included. Pre-DM was defined as a fasting glucose level of 100-125 mg/dL confirmed within a year by a repeated fasting glucose or hemoglobin A1c measurement of 5.7%-6.4%. Incident proteinuria was defined as a urine protein-to-creatinine ratio (UPCR) >200 mg/g, confirmed within a year. We used Poisson regression models to determine whether incident proteinuria in participants with pre-DM differed by HIV serostatus and, among PWH, whether HIV-specific factors were related to incident proteinuria., Results: Between 2006 and 2019, among 1276 men with pre-DM, proteinuria developed in 128 of 613 PWH (21%) and 50 of 663 PWOH (8%) over a median 10-year follow-up. After multivariable adjustment, the incidence of proteinuria in PWH with pre-DM was 3.3 times (95% confidence interval, 2.3-4.8 times) greater than in PWOH (P < .01). Among PWH, current CD4 cell count <50/µL (P < .01) and current use of protease inhibitors (P = .03) were associated with incident proteinuria, while lamivudine and integrase inhibitor use were associated with a lower risk., Conclusions: Among men with pre-DM, the risk of incident proteinuria was 3 times higher in PWH. Strategies to preserve renal function are needed in this population., Competing Interests: Potential conflicts of interest. L. S. declares consulting fees, support for attending meetings, and payment for presentation from Gilead Sciences, ViiV Healthcare, and Merck, outside the present work. A. G. A. declares a National Heart, Lung, and Blood Institute grant paid to her institution. F. J. P. declares payment from ViiV, Gilead Sciences, Janssen, Merck, and EMD Serono, outside the present work. J. W. M. declares a NIH/NHLBI research grant to the University of Pittsburgh and is an American Heart Association committee member. J. E. L. declares research support from Gilead Sciences, Pfizer, Oncoimmune, and CytoDyn, all paid to her institution; consulting fees for Theratechnologies; and stock options from CytoDyn. T. T. B. declares consulting fees from Merck, Janssen, Gilead Sciences, and ViiV Healthcare, outside the present work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Importance: Despite aging-related comorbidities representing a growing threat to quality-of-life and mortality among persons with HIV (PWH), clinical guidance for comorbidity screening and prevention is lacking. Understanding comorbidity distribution and severity by sex and gender is essential to informing guidelines for promoting healthy aging in adults with HIV., Objective: To assess the association of human immunodeficiency virus on the burden of aging-related comorbidities among US adults in the modern treatment era., Design, Setting, and Participants: This cross-sectional analysis included data from US multisite observational cohort studies of women (Women's Interagency HIV Study) and men (Multicenter AIDS Cohort Study) with HIV and sociodemographically comparable HIV-seronegative individuals. Participants were prospectively followed from 2008 for men and 2009 for women (when more than 80% of participants with HIV reported antiretroviral therapy use) through last observation up until March 2019, at which point outcomes were assessed. Data were analyzed from July 2020 to April 2021., Exposures: HIV, age, sex., Main Outcomes and Measures: Comorbidity burden (the number of total comorbidities out of 10 assessed) per participant; secondary outcomes included individual comorbidity prevalence. Linear regression assessed the association of HIV status, age, and sex with comorbidity burden., Results: A total of 5929 individuals were included (median [IQR] age, 54 [46-61] years; 3238 women [55%]; 2787 Black [47%], 1153 Hispanic or other [19%], 1989 White [34%]). Overall, unadjusted mean comorbidity burden was higher among women vs men (3.4 [2.1] vs 3.2 [1.8]; P = .02). Comorbidity prevalence differed by sex for hypertension (2188 of 3238 women [68%] vs 2026 of 2691 men [75%]), psychiatric illness (1771 women [55%] vs 1565 men [58%]), dyslipidemia (1312 women [41%] vs 1728 men [64%]), liver (1093 women [34%] vs 1032 men [38%]), bone disease (1364 women [42%] vs 512 men [19%]), lung disease (1245 women [38%] vs 259 men [10%]), diabetes (763 women [24%] vs 470 men [17%]), cardiovascular (493 women [15%] vs 407 men [15%]), kidney (444 women [14%] vs 404 men [15%]) disease, and cancer (219 women [7%] vs 321 men [12%]). In an unadjusted model, the estimated mean difference in comorbidity burden among women vs men was significantly greater in every age strata among PWH: age under 40 years, 0.33 (95% CI, 0.03-0.63); ages 40 to 49 years, 0.37 (95% CI, 0.12-0.61); ages 50 to 59 years, 0.38 (95% CI, 0.20-0.56); ages 60 to 69 years, 0.66 (95% CI, 0.42-0.90); ages 70 years and older, 0.62 (95% CI, 0.07-1.17). However, the difference between sexes varied by age strata among persons without HIV: age under 40 years, 0.52 (95% CI, 0.13 to 0.92); ages 40 to 49 years, -0.07 (95% CI, -0.45 to 0.31); ages 50 to 59 years, 0.88 (95% CI, 0.62 to 1.14); ages 60 to 69 years, 1.39 (95% CI, 1.06 to 1.72); ages 70 years and older, 0.33 (95% CI, -0.53 to 1.19) (P for interaction = .001). In the covariate-adjusted model, findings were slightly attenuated but retained statistical significance., Conclusions and Relevance: In this cross-sectional study, the overall burden of aging-related comorbidities was higher in women vs men, particularly among PWH, and the distribution of comorbidity prevalence differed by sex. Comorbidity screening and prevention strategies tailored by HIV serostatus and sex or gender may be needed.

Background: The 2013 Pooled Cohort Equations (PCEs) have underestimated cardiovascular disease (CVD) events among persons with HIV (PWH). We evaluate whether the addition of frailty improves PCE's ability to estimate CVD risk among aging PWH., Setting: Multicenter study., Methods: We assessed baseline frailty and 5-year atherosclerotic CVD risk using PCEs for participants in the AIDS Clinical Trials Group A5322 observational study. The primary outcome was incident CVD. We fit Cox proportional hazards regression models for incident CVD with (1) PCEs alone and (2) PCEs and frailty together (which included separate models for frailty score, frailty status, slow gait speed, and weak grip strength). We evaluated discrimination ability for the models with and without frailty by comparing their areas under receiver operating characteristic curve (AUCs) and Uno C-statistics, as well as by calculating the net reclassification improvement and integrated discrimination improvement., Results: The analysis included 944 A5322 participants (759 men, 185 women, median age 50 years, 47% White non-Hispanic). Thirty-nine participants experienced incident CVD during the study period. PCEs predicted 5-year CVD risk in all models. With frailty score, frailty status, slow gait speed, or weak grip strength added, the AUC and C-statistics were relatively unchanged, and the NRI and integrated discrimination improvement indicated little improvement in model discrimination. However, frailty score independently predicted CVD risk [frailty score: hazard ratio = 1.30, 95% confidence interval (CI) = 1.00 to 1.70, P = 0.05]., Conclusions: Frailty did not improve the predictive ability of PCEs. Baseline PCEs and frailty score independently predicted CVD. Incorporation of frailty assessment into clinical practice may provide corroborative and independent CVD risk estimation., Competing Interests: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. K.M.E. has received grant support from Gilead Sciences and has served on advisory panels for ViiV and Theratechnologies. S.L.K. has received grant support from Gilead Sciences. F.J.P. has received personal fees from Gilead Sciences, Janssen Pharmaceuticals, Merck and Co., and ViiV. All other authors report no potential conflicts of interest. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636, UM1 AI106701, and UM1 AI069494. This research is also supported in part by NIA AG054366. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The clinical epidemiology of treated HIV infection in the United States has dramatically changed in the past 25 years. Few sources of longitudinal data exist for people with HIV (PWH) spanning that period. Cohort data enable investigating new exposure and disease associations and monitoring progress along the HIV care continuum., Methods: We synthesized key published findings and conducted primary data analyses in the HIV Outpatient Study (HOPS), an open cohort of PWH seen at public and private HIV clinics since 1993. We assessed temporal trends in health outcomes (1993-2017) and mortality (1994-2017) for 10 566 HOPS participants., Results: The HOPS contributed to characterizing new conditions (eg, lipodystrophy), demonstrated reduced mortality with earlier HIV treatment, uncovered associations between select antiretroviral agents and cardiovascular disease, and documented remarkable shifts in morbidity from AIDS opportunistic infections to chronic noncommunicable diseases. The median CD4 cell count of participants increased from 244 cells/mm 3 to 640 cells/mm 3 from 1993 to 2017. Mortality fell from 121 to 16 per 1000 person-years from 1994 to 2017 ( P  < .001). In 2010, 83.7% of HOPS participants had a most recent HIV viral load <200 copies/mL, compared with 92.2% in 2017., Conclusions: Since 1993, the HOPS has been detecting emerging issues and challenges in HIV disease management. HOPS data can also be used for monitoring trends in infectious and chronic diseases, immunologic and viral suppression status, retention in care, and survival, thereby informing progress toward the Ending the HIV Epidemic initiative., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2020.)

Background: The objective of this study was to investigate whether 100% antiretroviral therapy (ART) adherence in men with HIV (MWH) is associated with normalization of concentrations of biomarkers of inflammation and immune activation compared with HIV-uninfected men., Methods: We analyzed person-visits with available biomarker data from the Multicenter AIDS Cohort Study (MACS) among MWH receiving ART with HIV RNA <50 copies/mL and among HIV-uninfected men. Self-reported adherence was classified as 100% if no missed ART doses in the past 4 days were reported. We evaluated associations between ART adherence and concentrations of 24 serum biomarkers compared with HIV-uninfected visits using a generalized gamma model, adjusting for potential confounders., Results: Person-visits (2565 from MWH reporting 100% ART adherence and 1588 from HIV-uninfected men) from a total of 1469 men were included in the analysis. Serum concentrations of interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), IL-1β, interferon-γ (IFN-γ), chemokine C-C motif ligand 2 (CCL2), and CCL14 from person-visits among MWH who reported 100% adherence were similar to HIV-uninfected person-visits. Comparatively higher concentrations of 11 biomarkers and lower concentrations of 7 biomarkers were observed in person-visits from MWH who reported 100% ART adherence, compared with HIV-uninfected person-visits., Conclusions: Although MWH with virologic suppression who reported 100% ART adherence exhibited overall higher concentrations of biomarkers of inflammation and immune activation compared with HIV-uninfected men, some biomarker concentrations were similar in both groups. These findings suggest that optimal ART adherence could have clinical implications beyond achieving and sustaining viral suppression., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease worldwide. Elevated sex hormone-binding globulin (SHBG) levels have been observed in the setting of HIV and may protect against some metabolic disorders. We aimed to investigate whether higher SHBG levels may protect against NAFLD in men with/without HIV., Methods: NAFLD was assessed using noncontrast computed tomography in 530 men in the Multicenter AIDS Cohort Study (MACS) who drank <3 alcoholic drinks/d and were uninfected with chronic hepatitis C or B (340HIV+, 190HIV-). Morning serum samples were tested for SHBG, total testosterone (TT), and adiponectin. Multivariable logistic regression was used to assess associations between HIV, SHBG, TT, adiponectin, and NAFLD., Results: Median SHBG was highest among HIV+/NAFLD- men and lowest among HIV-/NAFLD+ men. Adjusted for demographics, HIV, visceral adiposity, HOMA-IR, TT, and PNPLA3 genotype, higher SHBG was associated with lower odds of NAFLD (odds ratio [OR], 0.52 per doubling; 95% confidence interval [CI], 0.34-0.80). In separate multivariable models without SHBG, HIV (OR, 0.46; 95% CI, 0.26-0.79) and higher adiponectin (OR, 0.66 per doubling; 95% CI, 0.49-0.89) were associated with lower NAFLD odds, whereas TT was not significantly associated (OR, 0.74 per doubling; 95% CI, 0.53-1.04). Adjusting for SHBG attenuated the associations of HIV (OR, 0.61; 95% CI, 0.34-1.08) and adiponectin (OR, 0.74; 95% CI, 0.54-1.02) with NAFLD., Conclusions: SHBG levels were higher among HIV+ men, were independently associated with lower NAFLD, and could partially explain the associations of HIV and higher adiponectin with lower NAFLD in our cohort. These findings suggest that SHBG may protect against NAFLD, supporting further prospective and mechanistic studies., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Gait speed declines at a faster rate in persons with HIV (PWH) than in the general population but the risk factors associated with this decline are not well understood. In the AIDS Clinical Trials Group (ACTG) A5322 (HAILO, HIV Infection, Aging, and Immune Function Long-term Observational Study), an observational cohort study of PWH ≥40 years of age, those who developed slow gait during the first 3 years of follow-up were compared with persons who maintained normal speed. Associations with demographic and clinical covariates were assessed using multivariable logistic regression. Of 929 participants, 81% were men, 31% Black, and 20% Hispanic. Median age was 51 years [interquartile range (IQR) = 46-56]. At study entry, 92% had plasma HIV RNA <50 copies/mL with median CD4 count 631 cells/mm 3 (IQR = 458-840). At study entry, 7% of participants had slow gait, 16% had neurocognitive impairment (NCI), and 12% had diabetes. Over 3 years, 87% maintained normal gait speed, 3% maintained a slow gait, 6% developed a slow gait, and 4% improved from slow to normal gait speed. In multivariable models, hemoglobin A1C (HbA1C) percentage, per one unit increase [odds ratio (OR) = 1.36; 95% confidence interval (CI) = 1.03-1.81; p  = .033], NCI (OR = 3.47; 95% CI = 1.57-7.69 p  = .002), and black versus white race (OR = 2.45; 95% CI = 1.08-5.59; p  = .032) at entry were significantly associated with development of slow gait compared with those maintaining normal gait speed. The association between baseline HbA1C and development of slow gait speed highlights an intervenable target to prevent progression of physical function limitations.

Background: Falls and fall risk factors are common among people living with HIV (PLWH). We sought to identify fall risk factors among men with and without HIV., Methods: Men aged 50-75 years with (n = 279) and without HIV (n = 379) from the Bone Strength Substudy of the Multicenter AIDS Cohort Study were included. Multinomial logistic regression models identified risk factors associated with falling., Results: One hundred fourteen (41%) PLWH and 149 (39%) of uninfected men had ≥1 fall; 54 (20%) PLWH and 66 (17%) of uninfected men experienced ≥2 falls over 2 years. Five and 3% of PLWH and uninfected men, respectively, had a fall-related fracture (P = 0.34). In multivariate models, the odds of ≥2 falls were greater among men reporting illicit drug use, taking diabetes or depression medications, and with peripheral neuropathy; obesity was associated with a lower risk (all P < 0.05). In models restricted to PLWH, detectable plasma HIV-1 RNA, current use of efavirenz or diabetes medications, illicit drug use, and peripheral neuropathy were associated with greater odds of having ≥2 falls (P < 0.05). Current efavirenz use was associated with increased odds of an injurious fall; longer duration of antiretroviral therapy was protective (both P < 0.05). Greater physical activity was associated with lower risk of falls with fracture (P < 0.05)., Conclusions: Identified risk factors for recurrent falls or fall with fracture included low physical activity, detectable HIV-1 RNA, use of efavirenz, or use of medications to treat diabetes and depression. Fall risk reduction should prioritize interventions targeting modifiable risk factors including increased physical activity, antiretroviral therapy adherence, and transition off efavirenz.

Polypharmacy is the concurrent use of five or more medications. We used group-based trajectory analysis to identify groups of non-HIV medication polypharmacy and investigate associated risk factors among HIV-positive and HIV-negative men in the Multicenter AIDS Cohort Study (MACS) from 2004 to 2016. Each participant was assigned to mutually exclusive groups based on their observed patterns of polypharmacy over time. Risk factors associated with membership with resulting groups were investigated using a multinomial generalized logit model with repeated measures. There were 3160 participants (54.3% HIV positive) included in the study. The overall prevalence of polypharmacy was 33.1% and was higher in HIV-positive than HIV-negative participants (36.2% vs. 30.0%; p  < 0.001). Four distinct groups of polypharmacy emerged over time among all participants and among HIV-positive participants only: (1) nonpolypharmacy, (2) slow increasing polypharmacy, (3) rapid increasing polypharmacy, and (4) sustained polypharmacy. Being HIV positive, being 50 years of age or older, having medication insurance coverage, and having increased health care use were positively associated with membership in groups with sustained or increasing polypharmacy. Half of participants in each analysis had membership in one of the three high polypharmacy groups. This study revealed that access to care, through medication insurance coverage and health care use, was a key driver of polypharmacy in this cohort. Further exploration of medically appropriate and inappropriate prescribing practices in the context of polypharmacy and its impact on health outcomes in this and other populations is warranted.

Background: Neurocognitive impairment (NCI) is strongly associated with frailty in people living with human immunodeficiency virus (PLWH); the overlap of frailty and NCI and the impact on health outcomes in PLWH are unknown., Methods: PLWH in a longitudinal, observational study of aging completed entry evaluations for frailty and NCI. Outcomes of falls (recurrent) increased limitations in independent activities of daily living (IADL), or mortality were combined. Poisson regression models estimated prevalence ratios (PR) for ≥1 outcome over 2 years., Results: Among 987 participants, the median age at entry was 51 years; 19% were female; the median CD4 count was 616 cells/µL; and HIV-1 RNA was <200 copies/mL in 94%. Most (79%) participants had neither frailty nor NCI; 2% had both; 4% frailty only; and 15% NCI only. Over 2 years of observation, 100 (10%) participants experienced recurrent falls; 175 (18%) had worsening IADL limitations; 17 (2%) died; and 254 (26%) experienced ≥1 poor health outcome. In adjusted models, frailty with NCI was associated with more than double the risk of a poor health outcome (PR 2.65; 95% CI 1.98, 3.54); a significant association was also seen with frailty alone (PR 2.26; 95%CI 1.71, 2.99) and NCI alone (PR 1.73; 95% CI 1.36, 2.20)., Conclusions: The presence of frailty with NCI was associated with a greater risk of falls, disability, or death in PLWH than NCI alone. Interventions that target prevention or reversal of both frailty and NCI (such as increased physical activity) may significantly limit poor health outcomes among PLWH.

HIV-infected men have increased rates of osteoporosis and fracture compared to HIV-uninfected men. Testosterone use among HIV-infected men is common. In HIV-uninfected men, testosterone increases bone mineral density (BMD), but its effects have not been evaluated in HIV-infected men. In a substudy of Multicenter AIDS Cohort Study (MACS), the Bone Strength Substudy (BOSS) enrolled 202 HIV-infected and 201 HIV-uninfected men aged between 50 and 69 years. Study participants underwent dual-energy X-ray absorptiometry (DXA) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) and detailed assessment of osteoporosis risk factors. We used multivariable linear regression to determine associations and 95% confidence intervals (CIs) between self-reported testosterone use and T-scores at the LS, TH, and FN after adjustment for demographics, behavioral covariates, comorbidities, and other traditional osteoporosis risk factors. HIV-infected men reported more frequent testosterone use (22% vs. 4%; p < .001) and had lower median BMD T-score at TH than HIV-uninfected men (0.0 vs. 0.3; p = .045) but similar T-scores at LS and FN. In the overall study population, testosterone use was associated with significantly greater BMD T-score at LS (0.68; 95% CI: 0.22-1.13). In HIV-infected men with virologic suppression, testosterone was significantly associated with higher BMD T-score at LS (0.95; 95% CI: 0.36-1.54) and TH (0.45; 95% CI: 0.04-0.86). Current testosterone use is common in HIV-infected men and was associated with higher BMD, compared to those not taking testosterone. Testosterone's role in reducing fracture risk in HIV-infected men should be investigated.

Background: In the Multicenter AIDS Cohort Study, we examined whether fibroblast growth factor-23 (FGF-23), a bone-derived phosphaturic hormone involved in bone metabolism, is associated with incident frailty. Furthermore, we examined whether this association differs by HIV serostatus and race., Methods: Of 715 men assessed for frailty and selected for FGF-23 measurements using stored blood samples (2007-2011), 512 men were nonfrail at/before the baseline visit. Frailty was defined by the presence of ≥3 of the following on 2 consecutive 6-month visits within 1 year: unintentional weight loss ≥10 pounds, weakness, slowness, low energy, and low physical activity. We determined the association of FGF-23 levels with incident frailty using proportional hazards models adjusting for sociodemographics, comorbidities, and kidney function., Results: Sixty-five percent were HIV-infected; 29% were black. Median baseline FGF-23 levels were lower in HIV-infected vs. HIV-uninfected men (33.7 vs. 39.9 rU/mL, P = 0.006) but similar by race. During a median follow-up of 6.6 years, 32 men developed frailty; they had higher baseline FGF-23 levels vs. men who remained nonfrail (45 vs. 36 rU/mL, P = 0.02). FGF-23 (per doubling) was associated with a 1.63-fold risk of frailty [95% confidence interval (CI): 1.19 to 2.23]; results did not differ by HIV serostatus. Conversely, FGF-23 was associated with a 2.72-fold risk of frailty among blacks (95% CI: 1.51 to 4.91) but had minimal association among nonblacks (hazard ratio = 1.26, 95% CI: 0.77 to 2.05; p-interaction = 0.024)., Conclusions: Among men with or at-risk of HIV infection, higher FGF-23 was associated with greater risk of frailty, particularly in blacks. The mechanisms by which FGF-23 may contribute to frailty warrant further study.

Objective: Ongoing HIV replication while receiving combination antiretroviral therapy (cART) may reduce survival. Viremia copy-years (VCY) has shown improved mortality risk prediction over single time-point viral load measures. However, the timing of a patient's viral load history most associated with later mortality has not been studied. Here we determined the optimal duration and temporality of viral load history for predicting mortality., Design: Survival analysis among HIV-positive men who initiated cART in the Multicenter AIDS Cohort Study (1995-2015)., Methods: VCY measures were derived from area-under-the-viral load-curve. The overall VCY based upon the complete post-cART viral load history was compared with 20 VCYs derived from viral loads assessed during different shorter time periods (the most recent 1-10 years and initial 1-10 years following cART initiation) for associations with mortality., Results: Each 10-fold increase in VCYs based on the most recent 3-8 years was significantly associated with 23-26% decrease in survival times, a magnitude of effect greater than that of the most recent viral load (16%). These associations were independent of CD4 cell count and single time-point viral loads. In addition, the degree of pre-cART immunodeficiency did not affect the mortality prognostic value of VCY based on viral loads in the most recent 3 years. Conversely, the overall VCY and VCYs based on viral loads immediately following cART initiation were not independent predictors of mortality., Conclusion: Among cART-treated men, VCY based upon viral loads in the recent 3 years (six viral loads) has a mortality prognostic value greater than that of the overall VCY and single time-point viral loads, making the former a more feasible measure for use.

The inflammatory context of HIV infection has been posited to contribute to the higher comorbidity risk noted in HIV-infected populations. One possible pathway may involve 1,25-dihydroxyvitamin D [1,25(OH) 2 D], which plays a wide biologic role in many tissues. We sought to investigate whether inflammation was associated with vitamin D metabolites in a cohort of HIV-infected (HIV+) men receiving treatment and HIV-uninfected (HIV-) men. Vitamin D metabolites, including 25-hydroxyvitamin D [25(OH)D] and 1,25(OH) 2 D, were measured along with 24 inflammatory markers among Multicenter AIDS Cohort Study participants. Exploratory factor analysis reduced inflammatory marker data to a smaller set of inflammatory processes (IPs). Multivariate linear regression was used to evaluate associations between vitamin D metabolites and IPs. There were 466 HIV+ and 100 HIV- men, who contributed 658 stored samples from 1998 to 2008. We found three IPs with IP 1 characterized by sTNF-R2, sIL-2Rα, sCD27, BAFF, sgp130, sCD14, CXCL10 (IP-10), and sIL-6R. While none of the three IPs was associated with 25(OH)D levels in either HIV+ or HIV-, higher levels of IP 1 were significantly associated with the reduced levels of 1,25(OH) 2 D in HIV+, and a similar although nonsignificant trend was seen in HIV-. The association between 1,25(OH) 2 D and inflammation found among HIV-infected men suggests a possible mechanism whereby inflammation leads to the increased comorbidity risk noted among HIV-infected individuals.

Background: Increasing body mass index (BMI) is generally associated with loss of metabolic health, although some obese individuals remain metabolically healthy. Among nonobese men, HIV infection has been associated with a lower prevalence of metabolic health., Methods: We conducted a cross-sectional analysis of 470 HIV-infected and 368 HIV-uninfected men enrolled in the Multicenter AIDS Cohort Study Cardiovascular substudy. Circulating biomarker levels were compared by BMI category and by HIV serostatus. Poisson regression with robust variance determined associations between metabolic health and circulating inflammatory biomarker levels after adjusting for factors previously associated with metabolic health., Results: HIV-infected men were younger and less likely to be obese. Among HIV-infected, normal weight metabolically healthy men (compared to unhealthy) had significantly lower circulating levels of interleukin- (IL-) 6, soluble tumor necrosis factor receptors (sTNFR) I and II, and homeostatic model assessment of insulin resistance (HOMA-IR), higher adiponectin, less visceral fat, and more subcutaneous fat. Among HIV-uninfected normal weight men and obese men (regardless of HIV serostatus), metabolic health was associated only with higher levels of adiponectin, less visceral fat, and lower HOMA-IR values. In multivariate analyses restricted to HIV-infected men, lower hs-CRP, sTNFRI, sTNFRII, and HOMA-IR and higher adiponectin levels were associated with metabolic health. Additional adjustment for visceral adiposity did not alter results., Conclusions: Among HIV-infected normal weight men, metabolic health was associated with less systemic inflammation, a relationship that, among normal weight men, was unique to HIV+ men and did not exist among obese men of either HIV serostatus.

Rates of aging-related comorbidities, which require targeted medications to treat, have been shown to be increased among persons living with HIV compared with uninfected counterparts. Polypharmacy is generally defined as the concurrent use of 5 or more medications. We investigated polypharmacy prevalence for non-HIV medications over a 12-year period among HIV-positive and -negative participants in the Multicenter AIDS Cohort Study. Information regarding non-HIV medication use, HIV status, age, race/ethnicity, enrollment period, and medication insurance was obtained on 3,160 participants from semiannual visits between 2004 and 2016. Polypharmacy was defined as taking 5 or more non-HIV medications since the last health care visit. Generalized estimating equation models with repeated measures were produced overall and by HIV status to examine polypharmacy. The unadjusted prevalence of polypharmacy across all study visits was 18.6% and was higher among HIV-positive participants (24.4%) compared with HIV-negative participants (11.6%) (P < .0001). Among the 50 years and older age group, HIV-positive and HIV-negative participants had increases in polypharmacy over the observation period, from 38.4% to 46.8% (P = .0081) and from 16.7% to 46.0% (P < .0001), respectively. Among participants younger than 50, polypharmacy among HIV-positive participants remained stable (18.9% in 2004 to 17.3% in 2016; P = .5374) but increased among HIV-negative men (5.6% to 20.4%; P < .0001). After adjusting for age, race/ethnicity, and medication insurance, HIV-positive participants had a higher prevalence of polypharmacy than HIV-negative participants (25.3% vs 18.7%; P < .0001). Older age, white race, and having medication insurance coverage were also associated with greater polypharmacy. A convergence of polypharmacy prevalence was observed between HIV-positive and -negative participants at the end of observation. HIV-positive status was associated with an increased likelihood of polypharmacy, after adjusting for age, race/ethnicity, enrollment period, medication insurance, and study visit. Over time, polypharmacy prevalence increased among all participants, with converging rates between HIV-positive and -negative participants by the end of the observation period., Competing Interests: The authors have declared that no competing interests exist.

Background: Age-related gait speed decline is accelerated in men with human immunodeficiency virus (HIV). Mitochondrial genetic variation is associated with frailty and mortality in the general population and may provide insight into mechanisms of functional decline in people aging with HIV., Methods: Gait speed was assessed semiannually in the Multicenter AIDS Cohort Study. Mitochondrial DNA (mtDNA) haplogroups were extracted from genome-wide genotyping data, classifying men aged ≥50 years into 5 groups: mtDNA haplogroup H, J, T, Uk, and other. Differences in gait speed by haplogroups were assessed as rate of gait speed decline per year, probability of slow gait speed (<1.0 m/s), and hazard of slow gait using multivariable linear mixed-effects models, mixed-effects logistic regression models, and the Andersen-Gill model, controlling for hepatitis C virus infection, previous AIDS diagnosis, thymidine analogues exposure, education, body composition, smoking, and peripheral neuropathy. Age was further controlled for in the mixed-effects logistic regression models., Results: A total of 455 HIV-positive white men aged ≥50 years contributed 3283 person-years of follow-up. Among them, 70% had achieved HIV viral suppression. In fully adjusted models, individuals with haplogroup J had more rapid decline in gait speed (adjusted slopes, 0.018 m/s/year vs 0.011 m/s/year, pinteraction = 0.012) and increased risk of developing slow gait (adjusted odds ratio, 2.97; 95% confidence interval, 1.24-7.08) compared to those with other haplogroups., Conclusions: Among older, HIV-infected men, mtDNA haplogroup J was an independent risk factor for more rapid age-related gait speed decline.

Background: The process of obtaining approval for hepatitis C virus (HCV) treatment may be time consuming and complicated due to prior authorizations and the need to appeal denials. Pharmacists are poised to play a critical role in the acquisition and management of oral direct acting antivirals (DAAs) for the treatment of HCV infection; however, the time expended in this activity requires assessment. Objective: The objective of this study was to assess time expenditures by pharmacists to acquire DAAs for HCV therapy. Methods: Patients were enrolled in the Northwestern University Viral Hepatitis Registry, a prospective, observational cohort of ambulatory, adult patients living with human immunodeficiency virus (HIV) coinfected with chronic hepatitis B and/or C virus, and recruited since 2013 from the Infectious Disease Center at Northwestern Memorial Hospital, Chicago, IL. Patients were included in the current study if they were referred to the pharmacist for HCV DAA acquisition, drug-drug interaction management, and adherence counseling between February 1, 2014, and April 30, 2015. Patient demographics, virus-specific characteristics, and time required to secure HCV DAA treatment, counsel patients, and follow-up therapy were collected. Results: Among 54 HIV/HCV coinfected patients referred for treatment, all eventually received approval for DAA therapy. However, 87% (n = 47) required prior authorization. Pharmacists dedicated 2.1 hours/patient (interquartile range 1.5-2.8 hours; range 0.75-6.5 hours) to manage DAA therapy. Conclusion: Successful acquisition of HCV DAA therapy relied heavily on pharmacist effort, reflecting the vital role that pharmacists play in this process. Dedicated resources for medication access should be considered to ensure timely DAA acquisition., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FJP is a consultant/speaker for the following companies: Gilead Sciences, Janssen Pharmaceuticals, Merck, and Bristol Meyers Squibb. The other authors have no conflicts of interest to declare., (© The Author(s) 2018.)

Background: There is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV., Methods: Incident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence., Results: Eight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the previous 6 months [aHR = 1.84 (1.17-2.91)]; and persisted for T1MI (aHR = 1.62 [1.01]) and T2MI [aHR = 2.11 (1.08-4.29)]. FRS did not modify the effect of ABC on MI (P = 0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome., Conclusions: Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk of ABC use-associated MIs.

Maximizing the rates of virologic suppression (VS) among gay, bisexual, and other men who have sex with men (MSM) is essential to limiting HIV morbidity and sexual transmission of HIV in the United States. We analyzed data for MSM of non-Hispanic white (white), non-Hispanic black (black), or Hispanic/Latino race/ethnicity in the HIV Outpatient Study (HOPS) at nine U.S. HIV clinics. VS (HIV RNA <50 copies/ml) was measured closest to January 1, 2015. We modeled factors associated with VS among persons prescribed antiretroviral therapy (ART) for ≥6 months and assessed VS for a subset of participants with behavioral interview data. Among 1,303 MSM studied, 24% were black and 11% were Hispanic/Latino. Fewer black than white or Hispanic/Latino MSM had any documented ART use history (92% vs. 99% and 94%, respectively), and fewer had VS (72% vs. 91% and 81%), p  < .001. In analyses of MSM prescribed ART, which adjusted for insurance type, duration of ART use, and CD4 + cell count, blacks had lower prevalence of VS than whites [adjusted prevalence ratio (PR) 0.87, confidence interval (95% CI) 0.81-0.93] and Hispanics/Latinos did not (PR 0.95, 95% CI 0.88-1.02). Among 331 MSM with interview data, 6% had no VS, but reported anal sex without a condom with an HIV-uninfected or unknown HIV serostatus male partner in the past 6 months. In this study of HIV-infected MSM, blacks had a significantly lower prevalence of VS than white men. Optimizing HIV care and prevention among all MSM will require addressing underlying risk factors and social determinants of health that contribute to racial/ethnic disparities in HIV outcomes.

[This corrects the article DOI: 10.1371/journal.pone.0189973.].

In the United States, women accounted for 19% of new HIV diagnoses in 2015 and were less likely to reach virologic suppression when compared to men. We assessed trends and disparities in virologic suppression among HIV-positive women to inform HIV treatment strategies. Data were from a prospective cohort of the HIV Outpatient Study and collected at nine United States HIV clinics. We included women aged ≥18 years, with ≥1 visit, who were prescribed antiretroviral therapy, and had ≥1 viral load test performed between 2010 and 2015. We defined virologic suppression as viral load <50 copies/mL and calculated adjusted prevalence ratios (aPR) with 95% confidence intervals (CI) for virologic suppression by race/ethnicity and year of measure. Generalized estimating equations were used for multivariable analyses to assess factors associated with virologic suppression. Among 809 women (median age = 44 years), 482 (60%) were black, 177 (22%) white, 150 (19%) Hispanic/Latina. Virologic suppression was less prevalent among black women (73%) compared with Hispanic/Latina women (83%) and white women (91%). In multivariable analyses, not achieving virologic suppression was more likely among black women (aPR = 2.13; CI = 1.50-3.02) or Hispanic/Latina women (aPR = 1.66; CI = 1.08-2.56) compared with white women, and among women who attended public clinics (aPR = 1.42; CI = 1.07-1.87) compared with those who attended a private clinic. Between 2010 and 2015, virologic suppression among HIV-positive women increased from 68% to 83%, but racial/ethnic disparities persisted. Black and Hispanic/Latina women had significantly lower rates of virologic suppression than white women. Interventions targeting virologic suppression improvement among HIV-positive women of color, especially those who attend public clinics, are warranted.

Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is common among HIV-infected (HIV+) adults. The Liver Fat Score (LFS) is a non-invasive, rapid, inexpensive diagnostic tool that uses routine clinical data and is validated against biopsy in HIV-uninfected (HIV-) persons. CT liver-to-spleen (L/S) attenuation ratio is another validated method to diagnose NAFLD. We compared NAFLD prevalence using the LFS versus L/S ratio among Multicenter AIDS Cohort Study participants to assess the LFS's performance in HIV+vs. HIV-men., Methods: In a cross-sectional analysis of men reporting<3 alcoholic drinks daily (308 HIV+, 218 HIV-), Spearman correlations determined relationships between LFS and L/S ratio by HIV serostatus. Multivariable regression determined factors associated with discordance in LFS- and L/S ratio-defined NAFLD prevalence., Results: NAFLD prevalence by LFS and L/S ratio were 28%/15% for HIV+men and 20%/19% for HIV-men, respectively. Correlations between LFS and L/S ratio were weaker among HIV+than HIV-men, but improved with increasing BMI and exclusion of HCV-infected men. LFS and L/S ratio discordance occurred more frequently and across BMI strata among HIV+men, but predominantly at BMI<30 kg/m 2 among HIV-men. In multivariate analysis, only lower total testosterone levels were significantly associated with discordance., Conclusion: NAFLD prevalence was similar by LFS and L/S ratio identification among HIV-men, but dissimilar and with frequent discordance between the two tests among HIV+men. As discordance may be multifactorial, biopsy data are needed to determine the best non-invasive diagnostic test for NAFLD in HIV+persons.

Vitamin D may play an important role in a range of disease processes. In the general population, lower vitamin D levels have been associated with kidney dysfunction. HIV-infected populations have a higher risk of chronic kidney disease. Few studies have examined the link between lower vitamin D levels and kidney function decline among HIV-infected persons. We investigated the associations of serum 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH) 2 D] with kidney function decline in a cohort of HIV-infected white and black men under highly active antiretroviral therapy treatment in the vitamin D ancillary study of the Multicenter AIDS Cohort Study. The associations of 25(OH)D and 1,25(OH) 2 D with annual change in estimated glomerular filtration rate (eGFR) were evaluated using linear mixed effects models. This study included 187 whites and 86 blacks with vitamin D measures and eGFR ≥60 ml/min/1.73 m 2 at baseline. Over a median follow-up of 8.0 years, lower 25(OH)D levels were significantly associated with faster eGFR decline in whites (adjusted annual change in eGFR, tertile 1: -2.06 ml/min/1.73 m 2 vs. tertile 3: -1.23 ml/min/1.73 m 2 , p trend .03), while no significant association was detected in blacks. Lower 1,25(OH) 2 D was associated with faster kidney function decline in both whites and blacks, although the estimates were not statistically significant. In conclusion, lower 25(OH)D levels were significantly associated with faster eGFR decline in a cohort of HIV-infected white men, but not in those with black ancestry. Further research is warranted to investigate the association of 25(OH)D and 1,25(OH) 2 D with kidney function decline in larger and ethnically diverse populations.

Background: Older human immunodeficiency virus (HIV)-infected adults may experience higher rates of frailty and disability than the general population. Improved understanding of the prevalence, risk factors, and types of impairment can better inform providers and the healthcare system., Methods: HIV-infected participants within the AIDS Clinical Trials Group A5322 HAILO study self-reported disability by the Lawton-Brody Instrumental Activities of Daily Living (IADL) Questionnaire. Frailty was measured by 4-m walk time, grip strength, self-reported weight loss, exhaustion, and low activity. Logistic regression models identified characteristics associated with any IADL impairment. Agreement between IADL impairment and frailty was assessed using the weighted kappa statistic., Results: Of 1015 participants, the median age was 51 years, 15% were aged ≥60 years, 19% were female, 29% black, and 20% Hispanic. At least 1 IADL impairment was reported in 18% of participants, most commonly with housekeeping (48%) and transportation (36%) and least commonly with medication management (5%). In multivariable models, greater disability was significantly associated with neurocognitive impairment, lower education, Medicare/Medicaid insurance (vs private/other coverage), smoking, and low physical activity. Although a greater proportion of frail participants had IADL impairment (52%) compared to non-frail (11%) persons, agreement was poor (weighted kappa <0.18, 95% confidence interval, 0.13, 0.23)., Conclusion: IADL disability occurs frequently among middle-aged and older HIV-infected adults on effective antiretroviral therapy. Potentially modifiable risk factors (smoking, physical activity) provide targets for interventions to maintain independent living. Systematic recognition of persons at greater risk for disability can facilitate connection to resources that may help preserve independence., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

We evaluated associations of serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH] 2 D) levels in a cohort of HIV-infected and HIV-uninfected men at risk for infection in the United States. Stored samples collected between 1999 and 2008 were tested for vitamin D metabolites between 2014 and 2015. Vitamin D deficiency was defined as a serum concentration of 25[OH]D <20 ng/ml. Multivariate models were used to assess associations of various demographic and clinical factors with vitamin D status. HIV-infected men on effective antiretroviral therapy (n = 640) and HIV-uninfected men (n = 99) had comparable levels of 25[OH]D and 1,25[OH] 2 D, and prevalences of vitamin D deficiency were 41% in HIV-infected and 44% in HIV-uninfected men, respectively. Self-reported black or other non-white race, obesity, and normal kidney function were significant predictors of vitamin D deficiency regardless of HIV serostatus. Lower CD4 + T cell count was associated with vitamin D deficiency in HIV-infected men, while current ritonavir use was protective. Self-reported black race was the only factor significantly associated with higher levels of 1,25[OH] 2 D (vs. whites; β = 4.85 pg/ml, p = .003). Levels of 1,25[OH] 2 D and 25[OH]D were positively correlated in HIV-infected men (β = 0.32 pg/ml, p < .001), but not in uninfected men (β = -0.09 pg/ml, p = .623; p < .05 for interaction). Vitamin D deficiency was prevalent regardless of HIV serostatus in this cohort, suggesting that HIV infection did not confer additional risk of deficiency in this cohort of well-treated HIV-infected men. However, HIV infection and race may have implications for vitamin D metabolism and 1,25[OH] 2 D levels.

Background: Lower muscle density on computed tomography (CT) provides a measure of fatty infiltration of muscle, an aspect of muscle quality that has been associated with metabolic abnormalities, weakness, decreased mobility, and increased fracture risk in older adults. We assessed the cross-sectional relationship between HIV serostatus, age, thigh muscle attenuation, and thigh muscle cross-sectional area (CSA)., Methods: Mean CT-quantified Hounsfield units (HU) of the thigh muscle bundle and CSA were evaluated in 368 HIV-infected and 145 HIV-uninfected men enrolled in the Multicenter AIDS Cohort Study (MACS) Cardiovascular Substudy using multivariable linear regression. Models all were adjusted for HIV serostatus, age, race, and body mass index (BMI); each model was further adjusted for covariates that differed by HIV serostatus, including insulin resistance, hepatitis C, malignancy, smoking, alcohol use, and self-reported limitation in physical activity., Results: HIV-infected men had greater thigh muscle CSA (p<0.001) but lower muscle density (p<0.001) compared to HIV-uninfected men. Muscle density remained lower in HIV-infected men (p = 0.001) when abdominal visceral adiposity, and thigh subcutaneous adipose tissue area were substituted for BMI in a multivariable model. Muscle density decreased by 0.16 HU per year (p<0.001) of increasing age among the HIV-infected men, but not in the HIV-uninfected men (HIV x age interaction -0.20 HU; p = 0.002)., Conclusion: HIV-infected men had lower thigh muscle density compared to HIV-uninfected men, and a more pronounced decline with increasing age, indicative of greater fatty infiltration. These findings suggest that lower muscle quality among HIV-infected persons may be a risk factor for impairments in physical function with aging., Competing Interests: TTB has served as a consultant to Gilead, Merck, ViiV Healthcare, Abbvie, EMD-Serono, and Theratechnologies. JEL has served as a consultant to Gilead Sciences and GlaxoSmithKline. KME has received research funding from Gilead and has served as a medical consultant to Theratechnologies. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background:  Human immunodeficiency virus (HIV)-infected individuals exhibit residual inflammation regardless of virologic suppression. We evaluated whether suboptimal adherence to combination antiretroviral therapy (cART) is associated with greater residual inflammation than optimal adherence, despite virologic suppression., Methods:  Longitudinal self-reported cART adherence data and serum concentrations of 24 biomarkers of inflammation and immune activation were measured at the same study visit in HIV RNA-suppressed (<50 copies/mL) HIV-infected men in the Multicenter AIDS Cohort Study from 1998 to 2009. Associations between dichotomized 6-month (<100% vs 100%) and categorized 4-day (<85%, 85%-99%, and 100%) cART adherence with biomarker concentrations were evaluated., Results:  A total of 912 men provided 2816 person-visits with documented plasma HIV RNA suppression. In adjusted models, person-visits at which <100% cART 6-month adherence was reported had higher concentrations of interleukin 2, 6, and 10, interferon γ, tumor necrosis factor α, and C-reactive protein than person-visits at which 100% cART adherence (P < .05) was reported. These same differences were observed in person-visits reporting <85% versus 100% 4-day cART adherence, but not in visits reporting 85%-99% versus 100% cART adherence. After adjustment for multiple comparisons, tumor necrosis factor α remained significantly higher (11% increase; P < .001) in person-visits at which <100% adherence was reported., Conclusions:  Higher concentrations of inflammatory biomarkers were observed among HIV RNA-suppressed men who reported <100% cART adherence than among more adherent men. Residual HIV replication (ie, below the limit of detection), more likely among men with suboptimal adherence, is a plausible mechanism. Whether improving cART adherence could affect residual inflammation and associated morbidity and mortality rates should be investigated., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background:  Cardiovascular disease (CVD) risk prediction tools are often applied to populations beyond those in which they were designed when validated tools for specific subpopulations are unavailable., Methods:  Using data from 2283 human immunodeficiency virus (HIV)-infected adults aged ≥18 years, who were active in the HIV Outpatient Study (HOPS), we assessed performance of 3 commonly used CVD prediction models developed for general populations: Framingham general cardiovascular Risk Score (FRS), American College of Cardiology/American Heart Association Pooled Cohort equations (PCEs), and Systematic COronary Risk Evaluation (SCORE) high-risk equation, and 1 model developed in HIV-infected persons: the Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study equation. C-statistics assessed model discrimination and the ratio of expected to observed events (E/O) and Hosmer-Lemeshow χ 2 P value assessed calibration., Results:  From January 2002 through September 2013, 195 (8.5%) HOPS participants experienced an incident CVD event in 15 056 person-years. The FRS demonstrated moderate discrimination and was well calibrated (C-statistic: 0.66, E/O: 1.01, P = .89). The PCE and D:A:D risk equations demonstrated good discrimination but were less well calibrated (C-statistics: 0.71 and 0.72 and E/O: 0.88 and 0.80, respectively; P < .001 for both), whereas SCORE performed poorly (C-statistic: 0.59, E/O: 1.72; P = .48)., Conclusions:  Only the FRS accurately estimated risk of CVD events, while PCE and D:A:D underestimated risk. Although these models could potentially be used to rank US HIV-infected individuals at higher or lower risk for CVD, the models may fail to identify substantial numbers of HIV-infected persons with elevated CVD risk who could potentially benefit from additional medical treatment., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Methods.  In a cross-sectional substudy of the Multicenter AIDS Cohort Study, noncontrast cardiac computed tomography (CT) scanning for coronary artery calcium (CAC) scoring was performed on all men, and, for men with normal renal function, coronary CT angiography (CTA) was performed. Associations between fat depots (visceral adipose tissue [VAT], abdominal subcutaneous adipose tissue [aSAT], and thigh subcutaneous adipose tissue [tSAT]) with coronary plaque presence and extent were assessed with logistic and linear regression adjusted for age, race, cardiovascular disease (CVD) risk factors, body mass index (BMI), and human immunodeficiency virus (HIV) parameters. Results.  Among HIV-infected men (n = 597) but not HIV-uninfected men (n = 343), having greater VAT was positively associated with noncalcified plaque presence (odds ratio [OR] = 1.04, P < .05), with a significant interaction (P < .05) by HIV serostatus. Human immunodeficiency virus-infected men had lower median aSAT and tSAT and greater median VAT among men with BMI <25 and 25-29.9 kg/m(2). Among HIV-infected men, VAT was positively associated with presence of coronary plaque on CTA after adjustment for CVD risk factors (OR = 1.04, P < .05), but not after additional adjustment for BMI. There was an inverse association between aSAT and extent of total plaque among HIV-infected men, but not among HIV-uninfected men. Lower tSAT was associated with greater CAC and total plaque score extent regardless of HIV serostatus. Conclusions.  The presence of greater amounts of VAT and lower SAT may contribute to increased risk for coronary artery disease among HIV-infected persons.

Recent evidence has shown a complex relationship between the gut microbiota, dietary nutrients, and cardiovascular disease (CVD). Trimethylamine-N-oxide (TMAO) production, initiated by the microbiota, has been associated with CVD events. We sought to test if this association exists in HIV-infected persons. After adjusting for aspirin use and CVD risk factors, HIV-infected men were more likely to have coronary stenosis in the second and third TMAO quartiles compared with the first quartile, but did not differ significantly in the fourth quartile. We found an inverted U-shaped association between TMAO levels and the presence of coronary artery stenosis among HIV-infected men.

Background: We characterized associations between smoking, alcohol, and recreational drug use and coronary plaque by HIV serostatus within the Multicenter AIDS Cohort Study (MACS)., Methods: MACS participants (N = 1005, 621 HIV+ and 384 HIV-) underwent non-contrast CT scanning to measure coronary artery calcium; 764 underwent coronary CT angiograms to evaluate plaque type and extent. Self-reported use of alcohol, tobacco, smoked/inhaled cocaine, methamphetamine, ecstasy, marijuana, inhaled nitrites, and erectile dysfunction drugs was obtained at semi-annual visits beginning 10 years prior to CT scanning. Multivariable logistic and linear regression models were performed, stratified by HIV serostatus., Results: Among HIV+ men, current smoking, former smoking, and cumulative pack years of smoking were positively associated with multiple coronary plaque measures (coronary artery calcium presence and extent, total plaque presence and extent, calcified plaque presence, and stenosis >50%). Smoking was significantly associated with fewer plaque measures of comparable effect size among HIV- men; current smoking and calcified plaque extent was the only such association. Heavy alcohol use (>14 drinks/week) was associated with stenosis >50% among HIV+ men. Among HIV- men, low/moderate (1-14 drinks/week) and heavy alcohol use were inversely associated with coronary artery calcium and calcified plaque extent. Few significant associations between other recreational drug use and plaque measures were observed., Conclusion: Smoking is strongly associated with coronary plaque among HIV+ men, underscoring the value of smoking cessation for HIV+ persons. Alcohol use may protect against coronary artery calcium and calcified plaque progression in HIV- (but not HIV+) men. Few positive associations were observed between recreational drug use and coronary plaque measures.

Background: Aging in males is associated with lower testosterone levels and a decrease in diurnal variation of testosterone secretion. Cross-sectional studies have shown lower than expected testosterone levels among HIV-infected men, but whether age-related changes in serum testosterone differ by HIV serostatus are not known., Methods: HIV-infected men from the Multicenter AIDS Cohort Study (MACS), age ≥ 45 years at highly active antiretroviral therapy initiation, who had ≥ 2 samples from the subsequent 10 years, were matched to HIV-uninfected men by age, race, MACS site, and calendar time of samples. Linear mixed-effects regression models were used to determine whether free testosterone (FT) and its rate of change differed by HIV serostatus., Results: One hundred eighty-two HIV-infected and 267 HIV-uninfected men were included, median age: 48.8 years (interquartile range: 45.8-53.4), median numbers of FT measurements per participant 4 (interquartile range: 3-5), 65% were drawn in the adjusted morning (AM). Mean-adjusted FT levels were lower among HIV-infected than HIV-uninfected men in AM samples {-6.1 ng/dL [95% confidence interval (CI): -9.8 to -2.4], P = 0.001}, but not in afternoon samples [-1.7 ng/dL (-6.0 to 2.6), P = 0.441]. The rate of FT decline with age did not differ by HIV serostatus: 9.2 ng/dL (95% CI: -13.4 to -5.0) per 10 years for HIV-infected vs. 7.9 ng/dL (95% CI: -10.2 to -5.5) for HIV-uninfected men, P = 0.578., Conclusions: FT decreased similarly with increasing age regardless of HIV serostatus. The lower AM, but not adjusted afternoon, FT levels among HIV-infected men compared with HIV-uninfected men suggest a loss of diurnal variation in FT levels among HIV-infected men.

Background: Although modern combination antiretroviral therapy (cART) regimens are better tolerated and less complex than earlier treatments, regimen modification or discontinuation remains a concern., Methods: We studied HIV Outpatient Study (HOPS) participants who initiated the first or second cART regimens during: 1996-1999, 2000-2003, 2004-2007, and 2008-2011. We analyzed regimen durability (time to regimen modification) and success (achieving undetectable plasma HIV RNA) for the first and second cART regimens using Kaplan-Meier curves and log-rank tests, and examined factors associated with durability and success of the first cART regimen using proportional hazards models., Results: Durability of cART was progressively longer for cART regimens initiated in more recent periods: median first cART regimen durations were 1.0, 1.1, 2.1, and 4.6 years in 1996-1999, 2000-2003, 2004-2007, and 2008-2011, and the median second cART durations were 0.9, 1.2, 2.8, and 3.9 years, respectively (both P < 0.001). Comparing 1996-1999 and 2008-2011, the percentage of patients who achieved an undetectable HIV RNA within 6 months of first cART initiation increased from 65% to 81% and from 63% to 80% on second cART (both P < 0.001). Among patients initiating first cART during 2008-2011, black non-Hispanic/Latino race/ethnicity and ≥ twice-daily dosing were significantly associated with higher rates of regimen modification (P < 0.05), and higher baseline HIV RNA levels were associated with failure to achieve an undetectable HIV RNA (P < 0.001)., Conclusions: Among HIV-infected U.S. adults in routine HIV care, durability of the first and second cART regimens and the likelihood of prompt virological suppression increased during 1996-2011, coincident with the availability of more tolerable, less complex cART options.

Context: Abnormalities in the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) axis have been observed in HIV-infected persons and have been implicated in cardiovascular disease (CVD) pathogenesis in the general population., Objective: To determine associations of serum OPG and RANKL concentrations with HIV infection and subclinical atherosclerosis., Design: Cross-sectional study nested within the Multicenter AIDS Cohort Study., Setting: Four US academic medical centers., Participants: There were 578 HIV-infected and 344 HIV-uninfected men., Main Outcome Measures: Coronary artery calcium (CAC) was measured by noncontrast cardiac computed tomography, and coronary stenosis and plaque characteristics (composition, presence, and extent) were measured by coronary computed tomography angiography. All statistical models were adjusted for traditional CVD risk factors., Results: OPG concentrations were higher, and RANKL concentrations were lower among HIV-infected men compared with HIV-uninfected men (P < 0.0001 each). Among HIV-infected men, higher OPG concentrations were associated with the presence of CAC, mixed plaque, and coronary stenosis >50%, but not with plaque extent. In contrast, among HIV-uninfected men, higher OPG concentrations were associated with the extent of both CAC and calcified plaque, but not with their presence. RANKL concentrations were not associated with plaque presence or the extent among HIV-infected men, but among HIV-uninfected men, lower RANKL concentrations were associated with greater extent of CAC and total plaque., Conclusions: OPG and RANKL are dysregulated in HIV-infected men, and their relationship to the presence and extent of subclinical atherosclerosis varies by HIV status. The role of these biomarkers in CVD pathogenesis and risk prediction may be different in HIV-infected men.

Objectives: Raltegravir (RAL)-containing antiretroviral therapy (ART) produced better immunologic and virologic responses than optimized background ART in clinical trials of heavily ART-experienced patients, but few data exist on long-term outcomes in routine HIV care., Methods: We studied ART-experienced HIV outpatient study (HOPS) participants seen at 10 US HIV-specialty clinics during 2007-2011.We identified patients who started (baseline date) either continuous ≥ 30 days of RAL-containing or RAL-sparing ART, and used propensity score (PS) matching methods to account for baseline clinical and demographic differences. We used Kaplan-Meier methods and log-rank tests for the matched subsets to evaluate probability of death, achieving HIV RNA < 50 copies/ml, and CD4 cell count (CD4) increase of ≥ 50 cells mm(- 3) during follow-up., Results: Among 784 RAL-exposed and 1062 RAL-unexposed patients, 472 from each group were matched by PS. At baseline, the 472 RAL-exposed patients (mean nadir CD4, 205 cells mm(- 3); mean baseline CD4, 460 cells mm(- 3); HIV RNA < 50 copies ml(- 1) in 61%; mean years on prescribed ART, 7.5) were similar to RAL unexposed. During a mean follow-up of over 3 years, mortality rates and immunologic and virologic trajectories did not differ between the two groups. Among patients with detectable baseline HIV RNA levels, 76% of RAL-exposed and 63% of RAL-unexposed achieved HIV RNA < 50 copies ml(- 1) (P = 0.51); 69 and 58%, respectively, achieved a CD4 increase ≥ 50 cells mm(- 3) (P = 0.70)., Discussion: In our large cohort of US ART-experienced patients with a wide spectrum of clinical history, similar outcomes were observed when prescribed RAL containing versus other contemporary ART.

Background: Monitoring antiretroviral drug resistance can inform treatment recommendations; however, there are few such data from US patients before they initiate ART., Methods: We analysed data from HIV Outpatient Study (HOPS) participants from nine US HIV clinics who were diagnosed with HIV infection during 1999-2011. Using the IAS-USA December 2010 guidelines, we assessed the frequency of major drug resistance mutations (mDRMs) related to antiretroviral agents in viral isolates from patients who underwent commercial genotypic testing (GT) for resistance before initiating ART. We employed general linear regression models to assess factors associated with having undergone GT, and then factors associated with having mDRM., Results: Among 1531 eligible patients, 758 (49.5%) underwent GT before first ART, increasing from 15.5% in 1999-2002 to 75.9% in 2009-11 (P < 0.001). GT was carried out a median of 1.2 months after the diagnosis of HIV. In adjusted regression analyses, patients with pre-ART CD4+ T lymphocyte counts ≥200 cells/mm(3) or with HIV RNA levels >5.0 log10 copies/mL and those with a first HOPS visit in 2006 or later were significantly (P < 0.05) more likely to have undergone GT. Of the 758 patients, 114 (15.0%) had mDRMs; mutations relating to NRTIs, NNRTIs and PIs were present in 8.0%, 7.1% and 2.6%, respectively. There was no temporal change in the frequency of mDRM, and mDRMs were associated with an HIV RNA level <4.0 log10 copies/mL., Conclusions: During 1999-2011, GT use among antiretroviral-naive patients became more common, but a quarter of patients in recent years remained untested. The frequency of mDRMs remained stable over time at about 15%., (Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Heightened immune activation among human immunodeficiency virus (HIV)-infected persons may contribute to atherosclerosis. We assessed associations of serologic markers of monocyte activation, soluble CD163 (sCD163) and soluble CD14 (sCD14), and monocyte chemoattractant protein 1 (CCL2) with subclinical atherosclerosis among men with and those without HIV infection in the Multicenter AIDS Cohort Study., Methods: We performed noncontrast computed tomography on 906 men (566 HIV-infected men and 340 HIV-uninfected men), 709 of whom also underwent coronary computed tomographic angiography. Associations between each biomarker and the prevalence of coronary plaque, the prevalence of stenosis of ≥50%, and the extent of plaque were assessed by logistic and linear regression, adjusting for age, race, HIV serostatus, and cardiovascular risk factors., Results: Levels of all biomarkers were higher among HIV-infected men, of whom 81% had undetectable HIV RNA, and were associated with lower CD4(+) T-cell counts. In the entire population and among HIV-infected men, higher biomarker levels were associated with a greater prevalence of coronary artery stenosis of ≥50%. Higher sCD163 levels were also associated with greater prevalences of coronary artery calcium, mixed plaque, and calcified plaque; higher CCL2 levels were associated with a greater extent of noncalcified plaque., Conclusions: sCD163, sCD14, and CCL2 levels were elevated in treated HIV-infected men and associated with atherosclerosis. Monocyte activation may increase the risk for cardiovascular disease in individuals with HIV infection., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

HIV is a pandemic disease, and many cellular and systemic factors are known to alter its infectivity and replication. Earlier studies had suggested that anemia is common in HIV-infected patients; however, higher iron was also observed in AIDS patients prior to the introduction of antiretroviral therapy (ART). Therefore, the relationship between iron and viral infection is not well delineated. To address this issue, we altered the levels of cellular iron in primary CD4(+) T cells and showed that higher iron is associated with increased HIV infection and replication. In addition, HIV infection alone leads to increased cellular iron, and several ART drugs increase cellular iron independent of HIV infection. Finally, HIV infection is associated with increased serum iron in HIV-positive patients regardless of treatment with ART. These results establish a relationship between iron and HIV infection and suggest that iron homeostasis may be a viable therapeutic target for HIV.

Background: Existing data suggest that human immunodeficiency virus (HIV)-infected African Americans carrying 2 copies of the APOL1 risk alleles have greater risk of kidney disease than noncarriers. We sought to determine whether HIV RNA suppression mitigates APOL1-related kidney function decline among African Americans enrolled in the Multicenter AIDS Cohort Study., Methods: We genotyped HIV-infected men for the G1 and G2 risk alleles and ancestry informative markers. Mixed-effects models were used to estimate the annual rate of estimated glomerular filtration rate (eGFR) decline, comparing men carrying 2 (high-risk) vs 0-1 risk allele (low-risk). Effect modification by HIV suppression status (defined as HIV type 1 RNA level <400 copies/mL for >90% of follow-up time) was evaluated using interaction terms and stratified analyses., Results: Of the 333 African American men included in this study, 54 (16%) carried the APOL1 high-risk genotype. Among HIV-infected men with unsuppressed viral loads, those with the high-risk genotype had a 2.42 mL/minute/1.73 m(2) (95% confidence interval [CI], -3.52 to -1.32) faster annual eGFR decline than men with the low-risk genotype. This association was independent of age, comorbid conditions, baseline eGFR, ancestry, and HIV-related factors. In contrast, the rate of decline was similar by APOL1 genotype among men with sustained viral suppression (-0.16 mL/minute/1.73 m(2)/year; 95% CI, -.59 to .27; P for interaction <.001)., Conclusions: Unsuppressed HIV-infected African Americans with the APOL1 high-risk genotype experience an accelerated rate of kidney function decline; HIV suppression with antiretroviral therapy may reduce these deleterious renal effects., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Generalized obesity has been associated with cognitive decline, a process potentially mediated by adipocytokines. The effects of regional adipose tissue (AT) on cognition, however, are not well understood. We explored cross-sectional relationships between regional AT, adipocytokines, inflammatory markers and neuropsychological (NP) test scores among HIV+ and HIV- men enrolled in the Multicenter AIDS Cohort Study., Methods: Visceral, subcutaneous abdominal and subcutaneous thigh AT areas were quantified by computed tomography (CT). NP tests (Trail Making Test parts A and B, and Symbol-Digit Modalities) obtained within 2 years of CT screened for psychomotor speed and executive function. Adiponectin, leptin, interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) were measured., Results: Of 509 HIV+ and 271 HIV- participants, HIV+ men (98% on antiretroviral therapy, 81% HIV-1 RNA<50 copies/ml) had lower median subcutaneous AT and adiponectin levels and higher hs-CRP levels, but visceral AT, body mass index, IL-6 and NP scores did not vary by HIV serostatus. In multivariable analysis, older age, ≤ high school education and African American race, but not AT area or site, were associated with worse NP test scores among all participants. In HIV+ only, higher adiponectin and IL-6 were associated with worse cognitive function independent of AT area. No HIV-specific factors were associated with NP test scores., Conclusions: Demographic factors were associated with NP test performance, but regional adiposity was not. In HIV+ only, higher adiponectin and IL-6 were associated with worse NP test scores, supporting a role for chronic inflammation and adipocytokine imbalance in neurocognitive decline in HIV+ persons.

Background: Identifying factors associated with mortality for HIV-infected patients with persistent viraemia despite antiretroviral (ARV) therapy may inform diagnostic and treatment strategies., Methods: We analysed data from viraemic triple-ARV-class-experienced HIV Outpatient Study patients seen during 1 January 1999 to 31 December 2012 who, despite treatment that included ARVs from three major drug classes [nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors and protease inhibitors (PIs)], had plasma HIV RNA levels [viral load (VL)] >1000 copies/mL ['triple ARV class failure' (TCF)]. The baseline was defined as the date of meeting the TCF criteria during 1999-2008. We identified factors associated with mortality using Cox regression., Results: Of 597 patients who met the TCF criteria (median follow-up after baseline 4.9 years), 115 (19.3%) died. Baseline factors associated with mortality were age per 10 years [hazard ratio (HR) 1.61, 95% CI 1.28-2.02], risk of HIV from use of injection drugs (HR 1.81, 95% CI 1.10-2.98), CD4+ T cell count <200 cells/mm(3) (HR 3.68, 95% CI 2.41-5.62), VL ≥5.0 log10 copies/mL (HR 2.91, 95% CI 1.88-4.49) and receiving a first combination ARV therapy regimen that was PI-based (HR 2.44, 95% CI 1.47-4.06); receiving a novel ARV agent during follow-up (HR 0.45, 95% CI 0.22-0.93) was protective. Genotypic resistance testing results were available for 274 (45.9%) of the TCF patients, of whom 47 (17.2%) died. In this group, factors associated with death were increasing age (HR 1.94, 95% CI 1.36-2.78, per 10 year increment), risk of HIV from use of injection drugs (HR 2.71, 95% CI 1.37-5.39), baseline VL ≥5.0 log10 copies/mL (HR 5.35, 95% CI 2.82-10.1) and receiving PI-based first combination ARV therapy regimen (HR 3.20, 95% CI 1.25-8.17). No HIV mutations or combinations of mutations were significantly associated with survival., Conclusions: Factors significantly associated with mortality risk among TCF patients who received ongoing ARV therapy included traditional clinical predictors but not the presence, type or number of HIV genetic mutations. The use of novel ARV drugs by these ARV therapy-experienced patients was associated with an improved survival., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) may increase the risk of fatty liver disease. We determined the prevalence of and risk factors for fatty liver by comparing HIV-infected men with HIV-uninfected men who have sex with men in the Multicenter AIDS Cohort Study (MACS)., Methods: In 719 MACS participants who consumed less than three alcoholic drinks daily, fatty liver was defined as a liver-to-spleen attenuation ratio <1 on noncontrast computed tomography (CT). We genotyped single nucleotide polymorphisms in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene and in other genes previously associated with nonalcoholic fatty liver disease. Risk factors for fatty liver were determined using multivariable logistic regression., Results: Among 254 HIV-uninfected men and 465 HIV-infected men, 56% were White with median age 53 years and median body mass index 25.8 kg/m(2). The vast majority of HIV-infected men (92%) were on ART, and 87% of the HIV-infected men were treated with a nucleoside reverse transcriptase inhibitor for a median duration of 8.5 years. Overall, 15% of the cohort had fatty liver, which was more common in the HIV-uninfected compared with the HIV-infected men (19 vs. 13%, P=0.02). In multivariable analysis, HIV infection was associated with a lower prevalence of fatty liver (odds ratio (OR)=0.44, P=0.002), whereas a higher prevalence of fatty liver was seen in participants with PNPLA3 (rs738409) non-CC genotype (OR=2.06, P=0.005), more abdominal visceral adipose tissue (OR=1.08 per 10 cm(2), P<0.001), and homeostatic model assessment of insulin resistance (HOMA-IR) ≥4.9 (OR=2.50, P=0.001). Among HIV-infected men, PNPLA3 (rs738409) non-CC genotype was associated with a higher prevalence of fatty liver (OR=3.30, P=0.001) and cumulative dideoxynucleoside exposure (OR=1.44 per 5 years, P=0.02)., Conclusions: CT-defined fatty liver is common among men at risk for HIV infection and is associated with greater visceral adiposity, HOMA-IR, and PNPLA3 (rs738409). Although treated HIV infection was associated with a lower prevalence of fatty liver, prolonged exposure to dideoxynucleoside analogs is associated with higher prevalence.