Safety and Immune Responses Following Anti-PD-1 Monoclonal Antibody Infusions in Healthy Persons With Human Immunodeficiency Virus on Antiretroviral Therapy.

Background: T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods: This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/µL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results: Five men were enrolled (median CD4+ count, 911 cells/µL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions: One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.

Sex Differences in Subclinical Atherosclerosis and Systemic Immune Activation/Inflammation Among People With Human Immunodeficiency Virus in the United States.

BACKGROUND: Among people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein. METHODS: REPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score. RESULTS: The primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055). CONCLUSIONS: Among US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015).

Liver Inflammation Is Common and Linked to Metabolic Derangements in Persons With Treated Human Immunodeficiency Virus (HIV).

BACKGROUND: We sought to characterize in people with human immunodeficiency virus (PWH) the potential etiologies of elevated alanine aminotransferase (ALT) levels, which are common and often unexplained. METHODS: Participants from the longitudinal observational AIDS Clinical Trials Group HAILO cohort without a history of hepatitis C virus (HCV) or hepatitis B virus (HBV) infection nor reported heavy alcohol use were included. Clinical and demographic characteristics, including medication use, the hepatic steatosis index (HSI), and metabolic syndrome (MetS) were compared between participants with and without ALT elevation. RESULTS: Six hundred sixty-two participants were included; 444 (67%) had ≥1 and 229 (35%) ≥2 consecutive ALT elevations during a median of 4.0 years of follow-up. HSI and Hispanic or other (non-White or Black) race/ethnicity were consistently associated with higher odds of abnormal ALT (odds ratio [OR] 1.1 for HSI as a continuous variable, OR 1.9-2.8 for Hispanic/other race/ethnicity for ≥1 or ≥2 ALT elevations); older age and current smoking were associated with lower odds of abnormal ALT. Associations with metabolic disease, as well as with incident HBV and HCV infection, were strengthened by restricting outcomes to persistent and higher degrees of ALT elevation. CONCLUSIONS: ALT elevation was common in this cohort of PWH and associated with metabolic disease and hepatic steatosis markers. Nonalcoholic fatty liver disease is likely a common cause of liver inflammation in PWH receiving suppressive antiretrovirals, deserving targeted diagnosis and intervention.

Cytomegalovirus Immunoglobulin G (IgG) Titer and Coronary Artery Disease in People With Human Immunodeficiency Virus (HIV).

BACKGROUND: Cytomegalovirus (CMV) infection is thought to result in increased immune activation in people with human immunodeficiency virus (HIV, PWH). Although some data have linked asymptomatic CMV infection to cardiovascular disease among PWH, it remains unknown whether CMV is associated with increased or high-risk coronary plaque. METHODS: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) enrolled PWH aged 40-75 years on stable antiretroviral therapy (ART) with low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk. Among a subset of US REPRIEVE participants, coronary plaque was assessed by coronary computed tomography angiography. Here, we assessed the relationship between CMV immunoglobulin G (IgG) titer and (1) levels of immune activation, (2) inflammatory biomarkers, and (3) coronary plaque phenotypes at study entry. RESULTS: Of 672 participants, mean age was 51 years, 83% were men, median ASCVD risk score was 4.5%, and 66% had current CD4+ T-cell count ≥500 cells/mm3. Higher CMV IgG quartile group was associated with older age and lower current and nadir CD4+ T-cell counts. CMV IgG titer was associated with specific inflammatory biomarkers (sCD163, MCP-1, interleukin [IL]-6, hsCRP) in univariate analysis, but not after controlling for HIV-specific factors. In contrast, CMV IgG titer was not associated with coronary artery disease indexes, including presence of plaque, coronary artery calcium (CAC) score >0, vulnerable plaque presence, or Leaman score >5. CONCLUSIONS: No meaningful association was seen between CMV IgG titer and coronary artery disease indexes among ART-treated PWH at study enrollment. Longitudinal assessments in REPRIEVE will determine the relationship of CMV IgG titer to plaque progression and cardiovascular events. CLINICAL TRIALS REGISTRATION: NCT02344290.

Bacterial Sexually Transmitted Infection Incidence Among Southern Men Who Have Sex With Men With Human Immunodeficiency Virus in the Treatment as Prevention Era, 2014-2019.

In this retrospective analysis of men who have sex with men with human immunodeficiency virus (HIV) in the South from 2014 through 2019, incident bacterial sexually transmitted infections (STIs) increased regardless of virologic control. Clinicians should prioritize STI screening and management in primary HIV care.

Factors Associated With Systemic Immune Activation Indices in a Global Primary Cardiovascular Disease Prevention Cohort of People With Human Immunodeficiency Virus on Antiretroviral Therapy.

BACKGROUND: Among antiretroviral therapy (ART)-treated people with human immunodeficiency virus (PWH), persistent systemic immune activation contributes to atherogenesis atherosclerotic, cardiovascular disease (CVD) events, and mortality. Factors associated with key immune activation indices have not previously been characterized among a global primary CVD prevention cohort of PWH. METHODS: Leveraging baseline Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) data, we evaluated factors associated with soluble CD14 (sCD14) and oxidized low-density lipoprotein (oxLDL). RESULTS: The primary analysis cohort included 4907 participants from 5 global-burden-of-disease regions (38% female, 48% Black, median age 50 years). In fully adjusted models for sCD14, female sex and White race (among those in high-income regions) were associated with higher sCD14 levels, while higher body mass index (BMI) and current use of nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor ART were associated with lower sCD14 levels. In fully adjusted models for oxLDL, male sex, residence in high-income regions, White race (among those in high-income regions), and higher BMI were associated with higher oxLDL levels. In a subanalysis cohort of 1396 women with HIV, increased reproductive age was associated with higher sCD14 levels but not with higher oxLDL levels. CONCLUSIONS: Factors associated with sCD14 and oxLDL, 2 key indices of immune-mediated CVD risk, differ. Future studies will elucidate ways in which medications (eg, statins) and behavioral modifications influence sCD14 and oxLDL and the extent to which dampening of these markers mediates CVD-protective effects. CLINICAL TRIALS REGISTRATION: NCT0234429.

Geographical Differences in the Self-Reported Functional Impairment of People With Human Immunodeficiency Virus (HIV) and Associations With Cardiometabolic Risk.

BACKGROUND: We sought to explore multinational differences in functional status by global burden of disease (GBD) regions in the REPRIEVE cohort. METHODS: REPRIEVE is a prospective, double-blind, randomized, placebo-controlled, multicenter, phase III primary cardiovascular prevention study of pitavastatin calcium vs placebo among people with human immunodeficiency virus (HIV, PWH) ages 40-75 on antiretroviral therapy (ART). GBD super regions were defined using World Health Organization classifications. Participants were categorized by impairment on the Duke Activity Status Instrument (DASI: none, some, moderate, severe). Logistic regression models examined risk factors and GBD regions associated with functional impairment. The association between functional impairment and cardiometabolic risk was also explored. RESULTS: Of 7736 participants, the majority were from high-income countries (n = 4065), were male (65%), and had received ART for ≥ 10 years. The median DASI score was 58.2 (interquartile range [IQR] 50.2, 58.2); 36% reported at least some impairment. In adjusted analyses, functional impairment was significantly more frequent among participants from Southeast/East Asia. Other factors associated with greater impairment included female sex, Black race, older age, current/former smoking, higher body mass index, use of ART for ≥ 10 years, and select ART regimens; differences were seen in risks across GBD regions. Functional impairment was associated with increased cardiometabolic risk. CONCLUSIONS: Over 1/3 of middle-aged and older PWH in a global cohort across diverse GBD regions demonstrate functional impairments. The associations between DASI and cardiometabolic risk suggest that a measure of functional status may improve risk prediction; these longitudinal associations will be further investigated over REPRIEVE trial follow-up.

Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults With Human Immunodeficiency Virus.

BACKGROUND: Inflammation is associated with end-organ disease and mortality for people with human immunodeficiency virus (PWH). Ruxolitinib, a Jak 1/2 inhibitor, reduces systemic inflammation for individuals without human immunodeficiency virus (HIV) and HIV reservoir markers ex vivo. The goal of this trial was to determine safety and efficacy of ruxolitinib for PWH on antiretroviral therapy (ART). METHODS: AIDS Clinical Trials Group (ACTG) A5336 was an open-label, multisite, randomized controlled trial (RCT). Participants were randomly assigned (2:1) using centralized software to ruxolitinib (10 mg twice daily) plus stable ART for 5 weeks vs ART alone, stratified by efavirenz use. Eligible participants were suppressed on ART for ≥2 years, without comorbidities, and had >350 CD4+ T cells/µL. Primary endpoints were premature discontinuation, safety events, and change in plasma interleukin 6 (IL-6). Secondary endpoints included other measures of inflammation/immune activation and HIV reservoir. RESULTS: Sixty participants were enrolled from 16 May 2016 to 10 January 2018. Primary safety events occurred in 2.5% (1 participant) for ruxolitinib and 0% for controls (P = .67). Three participants (7.5%) prematurely discontinued ruxolitinib. By week 5, differences in IL-6 (mean fold change [FC], 0.93 vs 1.10; P = .18) and soluble CD14 (mean FC, 0.96 vs 1.08; relative FC, 0.96 [90% confidence interval {CI}, .90-1.02]) levels for ruxolitinib vs controls was observed. Ruxolitinib reduced CD4+ T cells expressing HLA-DR/CD38 (mean difference, -0.34% [90% CI, -.66% to -.12%]) and Bcl-2 (mean difference, -3.30% [90% CI, -4.72% to -1.87%]). CONCLUSIONS: In this RCT of healthy, virologically suppressed PWH on ART, ruxolitinib was well-tolerated. Baseline IL-6 levels were normal and showed no significant reduction. Ruxolitinib significantly decreased markers of immune activation and cell survival. Future studies of Jak inhibitors should target PWH with residual inflammation despite suppressive ART. CLINICAL TRIALS REGISTRATION: NCT02475655.

Incident bone fracture and mortality in a large HIV cohort outpatient study, 2000-2017, USA.

We evaluated the association of bone fracture with mortality among persons with HIV, controlling for sociodemographic, behavioral, and clinical factors. Incident fracture was associated with 48% greater risk of all-cause mortality, underscoring the need for bone mineral density screening and fracture prevention. PURPOSE/INTRODUCTION: Low bone mineral density (BMD) and fracture are more common among persons with HIV (PWH) than those without HIV infection. We evaluated the association of bone fracture with mortality among PWH, controlling for sociodemographic, behavioral, and clinical factors. METHODS: We analyzed data from HIV Outpatient Study (HOPS) participants seen at nine US HIV clinics during January 1, 2000, through September 30, 2017. Incident fracture rates and post-fracture mortality were compared across four calendar periods. Cox proportional hazards analyses determined factors associated with all-cause mortality among all participants and those with incident fracture. RESULTS: Among 6763 HOPS participants, 504 (7.5%) had incident fracture (median age = 47 years) and 719 (10.6%) died. Of fractures, 135 (26.8%) were major osteoporotic (hip/pelvis, wrist, spine, arm/shoulder). During observation, 27 participants with major osteoporotic fractures died (crude mortality 2.97/100 person-years [PY]), and 48 with other site fractures died (crude mortality 2.51/100 PY). Post-fracture, age- and sex-adjusted all-cause mortality rates per 100 PY decreased from 8.5 during 2000-2004 to 1.9 during 2013-2017 (P<0.001 for trend). In multivariable analysis, incident fracture was significantly associated with all-cause mortality (Hazard Ratio 1.48, 95% confidence interval 1.15-1.91). Among 504 participants followed post-fracture, pulmonary, kidney, and cardiovascular disease, hepatitis C virus co-infection, and non-AIDS cancer, remained independently associated with all-cause mortality. CONCLUSIONS: Incident fracture was associated with 48% greater risk of all-cause mortality among US PWH in care, underscoring the need for BMD screening and fracture prevention. Although fracture rates among PWH increased during follow-up, post-fracture death rates decreased, likely reflecting advances in HIV care.

Cardiovascular Risk and Health Among People With Human Immunodeficiency Virus (HIV) Eligible for Primary Prevention: Insights From the REPRIEVE Trial.

BACKGROUND: In addition to traditional cardiovascular (CV) risk factors, antiretroviral therapy, lifestyle, and human immunodeficiency virus (HIV)-related factors may contribute to future CV events in persons with HIV (PWH). METHODS: Among participants in the global REPRIEVE randomized trial, we characterized demographics and HIV characteristics relative to ACC/AHA pooled cohort equations (PCE) for atherosclerotic CV disease predicted risk and CV health evaluated by Life's Simple 7 (LS7; includes smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and glucose). RESULTS: Among 7382 REPRIEVE participants (31% women, 45% Black), the median PCE risk score was 4.5% (lower and upper quartiles Q1, Q3: 2.2, 7.2); 29% had a PCE score <2.5%, and 9% scored above 10%. PCE score was related closely to known CV risk factors and modestly (<1% difference in risk score) to immune function and HIV parameters. The median LS7 score was 9 (Q1, Q3: 7, 10) of a possible 14. Only 24 participants (0.3%) had 7/7 ideal components, and 36% had ≤2 ideal components; 90% had <5 ideal components. The distribution of LS7 did not vary by age or natal sex, although ideal health was more common in low sociodemographic index countries and among Asians. Poor dietary and physical activity patterns on LS7 were seen across all PCE scores, including the lowest risk categories. CONCLUSIONS: Poor CV health by LS7 was common among REPRIEVE participants, regardless of PCE. This suggests a critical and independent role for lifestyle interventions in conjunction with conventional treatment to improve CV outcomes in PWH. Clinical Trials Registration: NCT02344290. AIDS Clinical Trials Group study number: A5332.

Patterns of Antiretroviral Therapy Use and Immunologic Profiles at Enrollment in the REPRIEVE Trial.

BACKGROUND: Patterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described. METHODS: The REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics. RESULTS: A total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index >25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status. CONCLUSIONS: There were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV. CLINICAL TRIALS REGISTRATION: NCT02344290.

Admixture Mapping of Subclinical Atherosclerosis and Subsequent Clinical Events Among African Americans in 2 Large Cohort Studies.

BACKGROUND: Local ancestry may contribute to the disproportionate burden of subclinical and clinical cardiovascular disease among admixed African Americans compared with other populations, suggesting a rationale for admixture mapping. METHODS AND RESULTS: We estimated local European ancestry (LEA) using Local Ancestry inference in adMixed Populations using Linkage Disequilibrium method (LAMP-LD) and evaluated the association with common carotid artery intima-media thickness (cCIMT) using multivariable linear regression analysis among 1554 African Americans from MESA (Multi-Ethnic Study of Atherosclerosis). We conducted secondary analysis to examine the significant cCIMT-LEA associations with clinical cardiovascular disease events. We observed genome-wide significance in relation to cCIMT association with the SERGEF gene (secretion-regulating guanine nucleotide exchange factor; ß=0.0137; P=2.98×10-4), also associated with higher odds of stroke (odds ratio=1.71; P=0.02). Several regions, in particular CADPS gene (Ca2+-dependent secretion activator 1) region identified in MESA, were also replicated in the ARIC cohort (Atherosclerosis Risk in Communities). We observed other cCIMT-LEA regions associated with other clinical events, most notably the regions harboring CKMT2 gene (creatine kinase, mitochondrial 2) and RASGRF2 gene (Ras protein-specific guanine nucleotide-releasing factor 2) with all clinical events except stroke, the LRRC3B gene (leucine-rich repeat containing 3B) with myocardial infarction, the PRMT3 gene (protein arginine methyltransferase 3) with stroke, and the LHFPL2 gene (lipoma high mobility group protein I-C fusion partner-like 2) with hard and all coronary heart disease. CONCLUSIONS: We identified several novel LEA regions, in addition to previously identified genetic variations, associated with cCIMT and cardiovascular disease events among African Americans.

Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption.

BACKGROUND: The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). METHODS: We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. RESULTS: A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 µg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus. CONCLUSIONS: VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).

Ambulatory Blood Pressure Monitoring in Individuals with HIV: A Systematic Review and Meta-Analysis.

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.

High Prevalence of Low Bone Mineral Density and Substantial Bone Loss over 4 Years Among HIV-Infected Persons in the Era of Modern Antiretroviral Therapy.

HIV-infected persons are living longer on combination antiretroviral therapy (cART) but experiencing more comorbidities including low bone mineral density (BMD). Using data from the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN Study), we determined the prevalence of low BMD (T-score below one standard deviation of the reference mean) and compared it with matched controls from the National Health and Nutrition Examination Survey (NHANES). We also assessed 4-year longitudinal BMD changes among participants virologically suppressed on cART. Of 653 participants included in this analysis (77% male, 29% black, median age 41 years, median CD4(+) cell count 464 cells/mm(3), 89% with HIV RNA <400 copies/ml), 51% and 10% had baseline osteopenia and osteoporosis, respectively. Low BMD at the femoral neck was significantly more prevalent than for the NHANES controls (47% versus 29%, p<0.001). Lower body mass index, nonwhite race, longer tenofovir exposure, older age, being unemployed or retired, and lower apolipoprotein E were independently associated with baseline osteoporosis. Among 170 participants virologically suppressed on cART and with longitudinal BMD data, 31% experienced substantial bone loss (≥5% BMD decline from baseline) over 4 years. Female sex, current smoking, and longer stavudine use were more common among participants who had substantial bone loss, although these variables failed to reach statistical significance. Low BMD was highly prevalent among HIV-infected persons. One-third of participants experienced substantial bone loss despite cART, suggesting the need for monitoring and potential clinical interventions.

Low bone mineral density and risk of incident fracture in HIV-infected adults.

BACKGROUND: Prevalence rates of low bone mineral density (BMD) and bone fractures are higher among HIV-infected adults compared with the general United States (US) population, but the relationship between BMD and incident fractures in HIV-infected persons has not been well described. METHODS: Dual energy X-ray absorptiometry (DXA) results of the femoral neck of the hip and clinical data were obtained prospectively during 2004-2012 from participants in two HIV cohort studies. Low BMD was defined by a T-score in the interval >-2.5 to <-1.0 (osteopenia) or ≤-2.5 (osteoporosis). We analysed the association of low BMD with risk of subsequent incident fractures, adjusted for sociodemographics, other risk factors and covariables, using multivariable proportional hazards regression. RESULTS: Among 1,006 participants analysed (median age 43 years [IQR 36-49], 83% male, 67% non-Hispanic white, median CD4(+) T-cell count 461 cells/mm(3) [IQR 311-658]), 36% (n=358) had osteopenia and 4% (n=37) osteoporosis; 67 had a prior fracture documented. During 4,068 person-years of observation after DXA scanning, 85 incident fractures occurred, predominantly rib/sternum (n=18), hand (n=14), foot (n=13) and wrist (n=11). In multivariable analyses, osteoporosis (adjusted hazard ratio [aHR] 4.02, 95% CI 2.02, 8.01) and current/prior tobacco use (aHR 1.59, 95% CI 1.02, 2.50) were associated with incident fracture. CONCLUSIONS: In this large sample of HIV-infected adults in the US, low baseline BMD was significantly associated with elevated risk of incident fracture. There is potential value of DXA screening in this population.

The Silent Epidemic - Frailty and Aging with HIV.

As the number of older adults with HIV increases, this population is experiencing an increased risk for frailty. While there is no single definition or diagnostic criteria for frailty, it is generally recognized as an accumulation of deficits in functional capacity and ability to perform activities of daily living. Frailty may be present in up to half of older adults living with HIV, and is associated with significant morbidity and mortality risk in this group. Frailty in HIV can either be transient, and linked to the status of HIV infection, or resemble a more typical gradual decline in functional capacity. Frailty risk in HIV may be exacerbated by mitochondrial dysfunction, chronic inflammation, and oxidative stress. Several tools have been developed and adapted to assess different domains of frailty, yet medical treatment of this condition can be complex and should consider management of polypharmacy as well as nutrition and exercise interventions. However, few concrete strategies have been developed to prevent or treat frailty in the context of HIV infection. This review summarizes what is currently known about the prevalence, diagnosis, and management of frailty among older adults living with HIV.

Human papillomavirus infection and cytologic abnormalities of the anus and cervix among HIV-infected women in the study to understand the natural history of HIV/AIDS in the era of effective therapy (the SUN study).

BACKGROUND: Human papillomavirus (HPV) infection of the cervix and related abnormal cervical cytology in HIV-infected women has been well described. Little is known about anal HPV infection in HIV-infected women. METHODS: The SUN Study is a prospective cohort study of 700 HIV-infected patients including 167 women. At baseline, patients completed a behavioral questionnaire and provided, among other samples, cervical and anal swabs for HPV detection and genotyping and for cytologic examination. Here, we present the available baseline data on the 167 women in the SUN study. RESULTS: Baseline results were available for 120 women (median age: 38 years, 57% non-Hispanic black, median CD4 cell count 444.5 cells/mm3), of whom, 77% were taking antiretroviral therapy. The prevalences in the anus and cervix of any HPV were 90% and 83%, respectively (P = 0.039), and of high-risk (HR) types 85% and 70%, respectively, (P = 0.001). There was no significant difference in the prevalences of abnormal cytology between the anus and cervix: 38% and 33%, respectively (P = 0.217). Although the presence of abnormal cervical cytology was associated with the presence of abnormal anal cytology (relative risk: 1.7, P = 0.024), its sensitivity (52.5%) and positive predictive value positive (45.6%) for identifying women with abnormal anal cytology were poor. A history of anal sex was not associated with anal HPV infection or abnormal anal cytology. CONCLUSIONS: In this cohort of HIV-infected women, anal HPV infection was more prevalent and diverse than cervical HPV infection. Anal cytologic abnormalities were as prevalent as cervical cytologic abnormalities, and although abnormal cervical cytology was predictive of abnormal anal cytology, results were not highly concordant. These data support the need for studies of anal cytologic screening of HIV-infected women.

FcRL6, a new ITIM-bearing receptor on cytolytic cells, is broadly expressed by lymphocytes following HIV-1 infection.

Fc receptor-like proteins (FcRLs) are a growing family of molecules homologous to FcgammaRI. Whereas all 7 previously reported Fc receptor homologs are expressed by B cells, here we report a new receptor, FcRL6, that is expressed by cytolytic cells including natural killer (NK) cells and effector and effector-memory CD8(+) T cells. FcRL6 contains a novel cytoplasmic cysteine-rich motif and recruits SHP-2 through a phosphorylated ITIM, indicating a potential signaling function in effector lymphocytes. In vitro, FcRL6 does not greatly influence NK-cell or CD8(+) T-cell-mediated cytotoxicity and has minimal impact on cytokine secretion. However, FcRL6 expression among T lymphocytes is greatly expanded in human immunodeficiency virus type 1 (HIV-1)-infected individuals, and includes not only effector and effector-memory CD8(+) T cells but also populations of CD4(+) T cells. Expansion of FcRL6-positive lymphocytes is not related to viral load, but is indicative of the dysregulated expansion of terminally differentiated effector lymphocyte populations in response to chronic HIV-1 infection and may serve as an important marker for chronic immune activation and for tracking the generation of effector cells following immune stimulation.