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This study reports that focused collaboration between infectious diseases and emergency medicine providers results in increased identification of patients with syphilis and HIV in the emergency department., Background Sexually transmitted infections (STIs) are a common reason for evaluation in the emergency department (ED). Given the overlapping risk factors for STIs, patients screened for gonorrhea and chlamydia should be tested for syphilis and HIV. Syphilis and HIV testing rates in the ED have been reported to be low. The study objective was to examine whether collaboration between emergency medicine (EM) and infectious disease (ID) providers improved syphilis and HIV testing in the ED. Methods A multidisciplinary team of EM and ID providers was formed to identify and address barriers to syphilis and HIV testing in the ED. Syphilis, HIV, chlamydia, and gonorrhea testing and infection rates were calculated and compared during 2 time periods: preintervention (January 1, 2012–December 30, 2017) and postintervention (November 1, 2018–November 30, 2019). We also extracted clinical and laboratory data from patients with positive syphilis and HIV results during the study period. Results The most commonly cited barrier to syphilis and HIV testing was concern about follow-up of positive results. Compared with the preintervention period, syphilis and HIV testing rates increased significantly in the postintervention period (incidence rate ratios, 30.70 [P < 0.0001] and 28.99 [P < 0.0001] for syphilis and HIV, respectively). The postintervention period was also associated with a significant increase in the identification of patients with positive syphilis and HIV results (incidence rate ratios, 7.02 [P < 0.0001] and 2.34 [P = 0.03], respectively). Conclusions Collaboration between EM and ID providers resulted in a significant increase in syphilis and HIV testing and diagnosis in the ED.

Background Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation—this metabolic shift may contribute to NCI and slowed gait speed in PWH. Methods Plasma citrate and succinate were assayed by liquid chromatography–mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed. Results Median age was 51 (range 40–78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P = .03), 0.07 SD lower time-updated NPZ-4 score (P = .01), and 0.02 m/s slower time-updated gait speed (P < .0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤ .01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline. Conclusions Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.

Background Neurocognitive impairment (NCI) and frailty are more prevalent among persons with human immunodeficiency virus (HIV, PWH) compared to those without HIV. Frailty and NCI often overlap with one another. Whether frailty precedes declines in neurocognitive function among PWH or vice versa has not been well established. Methods AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH. Participants undergo annual assessments for NCI and frailty. ACTG A5322 participants who developed NCI as indexed by tests of impaired executive functioning and processing speed during the first 3 years were compared to persons who maintained normal cognitive function; those who demonstrated resolution of NCI were compared to those who had persistent NCI. Participants were similarly compared by frailty trajectory. We fit multinomial logistic regression models to assess associations between baseline covariates (including NCI) and frailty, and associations between baseline covariates (including frailty) and NCI. Results In total, 929 participants were included with a median age of 51 years (interquartile range [IQR] 46–56). At study entry, 16% had NCI, and 6% were frail. Over 3 years, 6% of participants developed NCI; 5% developed frailty. NCI was associated with development of frailty (odds ratio [OR] = 2.06; 95% confidence interval [CI] = .94, 4.48; P = .07). Further adjustment for confounding strengthened this association (OR = 2.79; 95% CI = 1.21, 6.43; P = .02). Baseline frailty however was not associated with NCI development. Conclusions NCI was associated with increased risk of frailty, but frailty was not associated with development of NCI. These findings suggest that the presence of NCI in PWH should prompt monitoring for the development of frailty and interventions to prevent frailty in this population.

Background Longitudinal follow-up of older persons living with HIV is essential for the ascertainment of aging-related clinical and behavioral outcomes, and self-administered questionnaires are necessary for collecting behavioral information in research involving persons living with HIV. Web-based self-reported data collection results in higher data quality than paper-and-pencil questionnaires in a wide range of populations. The option of remote web-based surveys may also increase retention in long-term research studies. However, the acceptability and feasibility of web-based data collection in clinical research involving older persons living with HIV have never been studied. Objective This study aims to assess the acceptability and feasibility of a web-based survey to collect information on sexual, substance use, and physical activity behaviors; compare the data quality of the web-based survey with that of a paper-and-pencil questionnaire; and summarize web-based survey metrics. Methods This pilot study took place within the AIDS Clinical Trials Group A5322 study, a longitudinal cohort of men and women living with HIV (aged ≥40 years), followed at 32 clinical sites in the United States and Puerto Rico. A total of 4 sites participated in this study. A web-based survey was created using self-administered questionnaires typically completed in A5322 via paper and pencil. Pilot study participants completed these questionnaires via web-based survey at one research visit in lieu of paper-and-pencil administration. Two questions were added to assess feasibility, defined as participants’ perception of the ease of web-based survey completion (very hard, hard, easy, very easy), and their preferred format (computer or tablet, paper and pencil, no preference) for completing the questions in the future (acceptability). Feasibility and acceptability were summarized overall and by demographic and clinical characteristics; the proportion of evaluable data by web-based survey versus previously administered paper-and-pencil questionnaires (data quality) was compared for each question. Results Acceptability and feasibility were high overall: 50.0% (79/158) preferred computer or tablet, 38.0% (60/158) reported no preference, and 12.0% (19/158) preferred paper and pencil; 93.0% (147/158) reported survey completion easy or very easy. Older age was associated with lower odds of preferring computer or tablet to paper and pencil (odds ratio per 1-year increase in age: 0.91, 95% CI 0.85-0.98). Individuals who found the survey hard or very hard had a lower median neurocognitive test score than those who found it easy or very easy. Data quality with web-based survey administration was similar to or higher than that with paper-and-pencil administration for most questions. Conclusions Web-based survey administration was acceptable and feasible in this cohort of older adults living with HIV, and data quality was high. Web-based surveys can be a useful tool for valid data collection and can potentially improve retention in long-term follow-up studies.

BackgroundWe characterized associations between frailty and incident cardiovascular disease (CVD), diabetes mellitus (DM), bone disease, and mortality within a cohort of aging persons with human immunodeficiency virus (PWH).MethodsParticipants underwent frailty evaluations using the Fried frailty assessment (baseline and annually). Frailty was defined as having ≥3 frailty criteria. Clinical outcomes of mortality, CVD events, DM, and bone disease events were recorded throughout the study period (baseline to most recent study or clinic visit, or date of clinical outcome, whichever came first). Poisson regression models were used to evaluate associations between baseline frailty, change in frailty score over 48 weeks, and each clinical outcome.ResultsAmong 821 men and 195 women (median age 51 years), 62 (6%) were frail at baseline. Frailty scores increased by ≥1 component among 194 participants (19%) from baseline to 48 weeks. Baseline frailty was associated with an increased risk of incident CVD and DM, with a trend toward a significant association with bone events. Among frailty components, slow gait speed was associated with incident DM and borderline associated with incident CVD. An increase in frailty from baseline to week 48 was associated with mortality but not with the other clinical outcomes.ConclusionsBaseline frailty was associated with multiple adverse health outcomes (incident CVD, DM, and bone disease), while increase in frailty score was associated with mortality among PWH engaged in care. Incorporation of frailty assessments into the care of PWH may assist in improvement of functional status and risk stratification for age-related chronic diseases.

In this randomized pilot clinical trial, dolutegravir plus lamivudine was noninferior to continuation of standard 3-drug maintenance antiretroviral therapy. There was no emergence of drug resistance in the participant who experienced virologic failure while receiving dolutegravir plus lamivudine. Clinical Trials Registration {"type":"clinical-trial","attrs":{"text":"NCT02263326","term_id":"NCT02263326"}}NCT02263326

Objective:Both frailty and falls occur at earlier-than-expected ages among HIV-infected individuals, but the contribution of frailty-to-fall risk in this population is not well understood. We examined this association among participants enrolled in AIDS Clinical Trials Group (ACTG) A5322.Design:A pr

Background Although statins, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are generally well tolerated, the impact of these therapies individually or in combination on the change in neurocognitive function in persons with human immunodeficiency virus infection is unknown. Methods The study included participants in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort participants not receiving a statin or ACEI/ARB within 30 days of first neurologic assessment (baseline), with assessments by NPZ-3 (z score of averaged Trailmaking A and B tests and digit symbol test [DST]) from ≥2 measurements. Marginal structural models estimated the causal effect of statin or ACEI/ARB initiation on neurocognitive function; initial constant slope was assumed during the first year of treatment and a second constant slope thereafter. Results Of 3949 eligible participants, 16% started therapy with a statin, 11% with an ACEI/ARB, and 5% with both. Statin therapy had no significant effect on the composite NPZ-3 (primary outcome), Trailmaking B test, or DST. A small, nonsignificant positive effect on the Trailmaking A test was seen during year 1 (estimate, 0.088; 95% confidence interval, -.010 to .187; P = .08) and a small but significant negative effect (-0.033; -.058 to -.009; P = .007) in each subsequent year. ACEI/ARB therapy had a significant negative effect on the DST (-0.117; 95% confidence interval, -.217 to .016; P = .02) during year 1 but minimal effect in subsequent years or on other neurocognitive domains. Conclusions In summary, although modest declines in neurocognitive performance were seen in single domains with statin or ACEI/ARB therapy, we did not find consistent evidence that statins or ACEI/ARB have an effect on global neurocognitive function. Future studies should focus on long-term neurocognitive effects.

Mental health conditions are common among persons with HIV (PWH). An understanding of factors associated with prescription medication use for these conditions and clinical impact of the prescription medications may improve care of mental health disorders in PWH.Psychotropic medication use was examined among PWH within the AIDS Clinical Trials Group A5322 (HAILO) study. Multivariable logistic models and Cox regression models estimated the association between psychotropic medications (any/none) with baseline and incident slow gait (1 s/m) and neurocognitive impairment (NCI) for more than 4 years.Of 1035 participants, the median age was 51 years.81% were men, 30% black, non-Hispanic, and 20% Hispanic. Psychotropic medication use was similar between men (34%) and women (38%; P = 0.19). PWH using psychotropic medications had greater odds of baseline slow gait {odds ratio 1.61, [95% confidence interval (CI): 1.23 to 2.10]; P0.001}. Men but not women using psychotropic medications had an increased risk of developing slow gait [hazard ratio 1.85; (1.29 to 2.65) vs 0.77; (CI: 0.35 to 1.68), P interaction = 0.045]. The sex-specific odds ratios for medication use and NCI were qualitatively but not statistically different [men: 1.79; (1.14-2.80); women: 1.27; (0.56-2.90); P interaction = 0.47]. Psychotropic medication use was associated with an increased risk of incident NCI [hazard ratio 2.18; (95% CI: 1.23 to 3.84), P = 0.007] in both men and women.Psychotropic medications are associated with impairment in functional outcomes of aging, with a greater risk of baseline NCI and incident slow gait among men. Further investigation is needed to optimize outcomes in PWH and prescription of psychotropic medications among both men and women.

AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00118898","term_id":"NCT00118898"}}NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (ka), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 2.87 h−1, CL/F = 37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.

Key Points Question What is the extent of coronary artery disease among people with well-controlled HIV and low to moderate risk of atherosclerotic cardiovascular disease (ASCVD), and how is coronary artery disease associated with traditional risk, inflammatory, and immune activation indices? Findings In this cohort study of 755 people with HIV, coronary plaque was highly prevalent. Critical stenosis was rare, but higher-risk plaque features, including vulnerable plaque and high Leaman scores, were seen in approximately one-fifth of participants; plaque indices were associated with ASCVD risk scores and, independently, indices of inflammation and immune activation. Meaning These findings suggest that people with HIV at low to moderate risk of cardiovascular disease have a significant prevalence of coronary plaque associated with inflammation and immune activation markers., This cohort study examines the prevalence of coronary artery disease (CAD) among adults with well-controlled HIV and low to moderate risk of atherosclerotic cardiovascular disease using computed tomography angiography and assessment of inflammation and immune activation biomarkers., Importance Cardiovascular disease (CVD) is increased among people with HIV (PWH), but little is known regarding the prevalence and extent of coronary artery disease (CAD) and associated biological factors in PWH with low to moderate traditional CVD risk. Objectives To determine unique factors associated with CVD in PWH and to assess CAD by coronary computed tomography angiography (CTA) and critical pathways of arterial inflammation and immune activation. Design, Setting, and Participants This cohort study among male and female PWH, aged 40 to 75 years, without known CVD, receiving stable antiretroviral therapy, and with low to moderate atherosclerotic cardiovascular disease (ASCVD) risk according to the 2013 American College of Cardiology/American Heart Association pooled cohort equation, was part of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), a large, ongoing primary prevention trial of statin therapy among PWH conducted at 31 US sites. Participants were enrolled from May 2015 to February 2018. Data analysis was conducted from May to December 2020. Exposure HIV disease. Main Outcomes and Measures The primary outcome was the prevalence and composition of CAD assessed by coronary CTA and, secondarily, the association of CAD with traditional risk indices and circulating biomarkers, including insulin, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL) 6, soluble CD14 (sCD14), sCD163, lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), and high-sensitivity C-reactive protein (hsCRP). Results The sample included 755 participants, with a mean (SD) age of 51 (6) years, 124 (16%) female participants, 267 (35%) Black or African American participants, 182 (24%) Latinx participants, a low median (interquartile range) ASCVD risk (4.5% [2.6%-6.8%]), and well-controlled viremia. Overall, plaque was seen in 368 participants (49%), including among 52 of 175 participants (30%) with atherosclerotic CVD (ASCVD) risk of less than 2.5%. Luminal obstruction of at least 50% was rare (25 [3%]), but vulnerable plaque and high Leaman score (ie, >5) were more frequently observed (172 of 755 [23%] and 118 of 743 [16%], respectively). Overall, 251 of 718 participants (35%) demonstrated coronary artery calcium score scores greater than 0. IL-6, LpPLA2, oxLDL, and MCP-1 levels were higher in those with plaque compared with those without (eg, median [IQR] IL-6 level, 1.71 [1.05-3.04] pg/mL vs 1.45 [0.96-2.60] pg/mL; P = .008). LpPLA2 and IL-6 levels were associated with plaque in adjusted modeling, independent of traditional risk indices and HIV parameters (eg, IL-6: adjusted odds ratio, 1.07; 95% CI, 1.02-1.12; P = .01). Conclusions and Relevance In this study of a large primary prevention cohort of individuals with well-controlled HIV and low to moderate ASCVD risk, CAD, including noncalcified, nonobstructive, and vulnerable plaque, was highly prevalent. Participants with plaque demonstrated higher levels of immune activation and arterial inflammation, independent of traditional ASCVD risk and HIV parameters.

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

Author(s): Schrack, Jennifer A; Althoff, Keri N; Jacobson, Lisa P; Erlandson, Kristine M; Jamieson, Beth D; Koletar, Susan L; Phair, John; Ferrucci, Luigi; Brown, Todd T; Margolick, Joseph B; Multicenter AIDS Cohort Study | Abstract: BackgroundGait speed predicts functional decline, disability, and death and is considered a biomarker of biological aging. Changes in gait speed in persons aging with HIV may provide an important method of gauging health and longevity in an under assessed population. The objective of this study was to evaluate and quantify the rate of gait speed decline in HIV-infected (HIV⁺) men compared with HIV-uninfected (HIV⁻) men.MethodsThe study was nested in the Multicenter AIDS Cohort Study. The primary outcome was usual gait speed in meters per second measured between 2007 and 2013. Differences in the rate of gait speed decline and the incidence of clinically slow gait (l1.0 m/s) were assessed using multivariate linear regression models and Cox proportional hazards models, respectively.ResultsA total of 2025 men (973 HIV⁺ and 1052 HIV⁻) aged 40 years and older contributed 21,187 person-visits (9955 HIV⁺ and 11,232 HIV⁻) to the analysis. Average gait speeds at the age 50 years were 1.24 and 1.19 m/s in HIV⁻ and HIV⁺ men, respectively (P l 0.001). In fully adjusted models, gait speed decline averaged 0.009 m/s per year after age 50 years (P l 0.001); this decline was 0.025 m/s per year greater in HIV⁺ men (P l 0.001). Moreover, HIV⁺ men had a 57% greater risk of developing clinically slow gait (adjusted hazard ratio = 1.57, 95% confidence interval: 1.27 to 1.91).ConclusionsThese findings indicate a faster rate of functional decline in HIV-infected men, suggesting greater risks of disability and death with advancing age.

Author(s): Tibuakuu, Martin; Zhao, Di; Saxena, Ankita; Brown, Todd T; Jacobson, Lisa P; Palella, Frank J; Witt, Mallory D; Koletar, Susan L; Margolick, Joseph B; Guallar, Eliseo; Korada, Sai Krishna C; Budoff, Matthew J; Post, Wendy S; Michos, Erin D | Abstract: BACKGROUND:HIV-infected individuals are at increased risk for both sarcopenia and cardiovascular disease. Whether an association between low muscle mass and subclinical coronary artery disease (CAD) exists, and if it is modified by HIV serostatus, are unknown. METHODS:We performed cross-sectional analysis of 513 male MACS participants (72% HIV-infected) who underwent mid-thigh computed tomography (CT) and non-contrast cardiac CT for coronary artery calcium (CAC) during 2010-2013. Of these, 379 also underwent coronary CT angiography for non-calcified coronary plaque (NCP) and obstructive coronary stenosis ≥50%. Multivariable-adjusted Poisson regression was used to estimate prevalence risk ratios of associations between low muscle mass (l20th percentile of the HIV-uninfected individuals in the sample) and CAC, NCP and obstructive stenosis. RESULTS:The prevalence of low thigh muscle mass was similar by HIV serostatus (20%). There was no association of low muscle mass with CAC or NCP. However, low thigh muscle mass was significantly associated with a 2.5-fold higher prevalence of obstructive coronary stenosis, after adjustment for demographics and traditional CAD risk factors [PR 2.46 (95% CI 1.51, 4.01)]. This association remained significant after adjustment for adiposity, inflammation, and physical activity. There was no significant interaction by HIV serostatus (p-interaction = 0.90). CONCLUSIONS:In this exploratory analysis, low thigh muscle mass was significantly associated with subclinical obstructive coronary stenosis. Additional studies involving larger sample sizes and prospective analyses are needed to confirm the potential utility of measuring mid-thigh muscle mass for identifying individuals at increased risk for obstructive CAD who might benefit from more aggressive risk factor management.

Author(s): Johs, Nikolas A; Wu, Kunling; Tassiopoulos, Katherine; Koletar, Susan L; Kalayjian, Robert C; Ellis, Ronald J; Taiwo, Babafemi; Palella, Frank J; Erlandson, Kristine M | Abstract: BackgroundOlder 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.MethodsHIV-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.ResultsOf 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 l0.18, 95% confidence interval, 0.13, 0.23).ConclusionIADL 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.

BACKGROUND Frailty is associated with immune activation and inflammation in the elderly general population, but whether this is true in the younger HIV-infected (HIV+) population is not known. METHODS We analyzed 24 serologic biomarkers of monocyte, T-cell, or B-cell activation in HIV- (n = 207) and HIV+ (n = 714; 75% virologically suppressed) men who have sex with men in the Multicenter AIDS Cohort Study (MACS) and were classified as frail or nonfrail according to expression or nonexpression of the frailty phenotype at 2 consecutive study visits. RESULTS After correction for multiple comparisons and adjustment for age, race, study site, and education, frailty in HIV+ men was significantly (P < 0.002) associated with higher levels of sCD14, sIL2Rα, sTNF-R2, IL-6, and TNF-α; the association with higher levels of C-reactive protein (CRP) approached significance (P = 0.003). After further adjustment for body mass index (BMI), smoking, and comorbidities, only the association with C-reactive protein was significant at P < 0.002, with levels approximately 50% higher in frail compared with nonfrail men. These conclusions were not altered by restricting the analysis to HIV+ men who were virologically suppressed. Among HIV- men, none of these markers differed significantly by frailty. CONCLUSIONS These data suggest that frailty in virologically suppressed HIV+ men was associated with immune activation beyond that due to treated HIV infection. The inflammatory markers associated with frailty were primarily products of activated monocytes/macrophages. Much, but not all, activation was accounted for by harmful behaviors and comorbidities. However, C-reactive protein, which is regulated by IL-6, was elevated in HIV+ frail men independent of these factors.

The impact of antiretroviral therapy (ART) on frailty among human immunodeficiency virus (HIV)-infected adults has not been well described. HIV-infected participants aged ≥40 years with initial ART receipt through a randomized, controlled AIDS Clinical Trials Group trial completed a frailty assessment. Ordinal logistic regression models examined factors associated with frailty. Of 1016 participants, 6%25 were frail, and 38%25 were prefrail. Frailty was associated with lower education, older age, Medicare/Medicaid, initial efavirenz, smoking, obesity, and neurocognitive impairment; physical activity and alcohol use were protective. The associations with ART require further investigation, and associations between frailty and modifiable factors provide targets for future interventions.

OBJECTIVE Laboratory monitoring is recommended during combination antiretroviral therapy (cART), but the pattern of detected abnormalities and optimal monitoring are unknown. We assessed laboratory abnormalities during initial cART in 2000-2010 across the United States. DESIGN Observational study in the Centers for AIDS Research Network of Integrated Clinical Systems Cohort. METHODS Among patients with normal results within a year prior to cART initiation, time to first significant abnormality was assessed by Kaplan-Meier curves stratified by event type, with censoring at first of regimen change, loss to follow-up, or 104 weeks. Incidence rates of first events were estimated using Poisson regression; multivariable analyses identified associated factors. Results were stratified by time (16 weeks) from therapy initiation. RESULTS A total of 3470 individuals contributed 3639 person-years. Median age, pre-cART CD4, and follow-up duration were 40 years, 206 cells/μl, and 51 weeks, respectively. Incidence rates for significant abnormalities (per 100 person-years) in the first 16 weeks post-cART initiation were as follows: lipid=49 [95% confidence interval (CI) 41-58]; hematologic=44 (40-49); hepatic=24 (20-27); and renal=9 (7-11), dropping substantially during weeks 17-104 of cART to lipid=23 (18-29); hematologic=5 (4-6); hepatic=6 (5-8); and renal=2 (1-3) (all P

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

Objective Body composition impacts physical function and mortality. We compared long-term body composition changes after antiretroviral therapy (ART) initiation in HIV-infected individuals to that in HIV-uninfected controls. Design Prospective observational study. Methods We performed dual-energy x-ray absorptiometry (DXA) approximately 7.5 years after initial DXA in available HIV-infected individuals who received DXAs during the randomized treatment trial AIDS Clinical Trials Group A5202. For controls, we used DXA results from HIV-uninfected participants in the Boston Area Community Health/Bone and Women's Interagency HIV Study cohorts. Repeated measures analyses compared adjusted body composition changes between HIV-infected and HIV-uninfected individuals. Multivariable analyses evaluated factors associated with body composition change in HIV-infected individuals. Results We obtained DXA results in 97 HIV-infected and 614 HIV-uninfected participants. Compared with controls, HIV-infected individuals had greater adjusted lean mass and total, trunk, and limb fat gain during the first 96 weeks of ART. Subsequently, HIV-infected individuals lost lean mass compared with controls. Total, trunk, and limb fat gains after 96 weeks of ART slowed in HIV-infected individuals but remained greater than in controls. Lower CD4 T-cell count was associated with lean mass and fat gain during the initial 96 weeks of ART, but subsequently no HIV-related characteristic was associated with body composition change. Conclusion Consistent with a 'return to health effect', HIV-infected individuals, especially those with lower baseline CD4 T-cell counts, gained more lean mass and fat during the first 96 weeks of ART than HIV-uninfected individuals. Continued fat gain and lean mass loss after 96 weeks may predispose HIV-infected individuals to obesity-related diseases and physical function impairment.

To determine the impact of highly active antiretroviral therapy (HAART) on liver disease, we analyzed changes in the aspartate aminotransferase to platelet ratio index (APRI) pre- and post-HAART initiation among 441 HIV-monoinfected and 53 HIV-viral hepatitis-coinfected men. Before HAART, APRI increased 17% and 34% among the HIV-monoinfected and coinfected men, respectively. With HAART initiation, APRI decreased significantly in men who achieved HIV RNA of

High prevalence of tobacco use and low success in quitting remain significant problems for reducing disease burden among HIV-infected persons. This study’s purpose was to examine participant responsiveness and tobacco dependence treatment adherence and their influences on tobacco abstinence among HIV-infected patients. This non-randomized study included HIV-infected smokers 18 years of age or older, who smoked at least 5 cigarettes per day, and had an interest in quitting smoking in the next 30 days. HIV-infected smokers (n = 247) received a 12-week tobacco dependence treatment intervention that included pharmacotherapy and telephone counseling. Younger age and non-White race were associated with lower adherence to pharmacotherapy. Younger age, non-White race, and increased monthly binge drinking were associated with lower adherence to telephone counseling. High participant responsiveness was associated with adherence to pharmacotherapy, counseling, and abstinence. Development and testing of interventions to improve adherence to evidence-based tobacco dependence treatment is warranted.

INTRODUCTION The prevalence of smoking is high among the human immunodeficiency virus (HIV)-infected population, yet there are few studies of tobacco dependence treatment in this population. This paper reports the safety of varenicline versus nicotine replacement therapy (NRT) and describes preliminary results about the effectiveness of varenicline versus NRT in HIV-infected smokers. METHODS Participants completed 12 weeks of telephone counseling and either varenicline or NRT. Varenicline was encouraged as the preferred intervention; NRT was used for those unable/unwilling to take varenicline. Adverse events (AEs), related to pharmacotherapy, were monitored. Biochemically confirmed abstinence at 3 months was examined. Inverse probability of treatment weighted logistic regression models was fit to compare participants on varenicline to those on NRT. RESULTS Among participants on varenicline (n = 118), the most common AEs were nausea, sleep problems, and mood disturbances. One person reported suicidal ideation; there were no cardiovascular complications. There were no differences in the varenicline AE profile between participants on combination antiretroviral therapy (ART) and those not on ART. The percentages of confirmed abstainers were 11.8% in the NRT group and 25.6% in the varenicline group. The odds of being abstinent were 2.54 times as great in the varenicline group compared with the NRT group in the propensity weighted model (95% CI 1.43-4.49). CONCLUSIONS In this preliminary study, the safety profile of varenicline among HIV-infected smokers resembles findings among smokers without HIV. In addition, varenicline may be more effective at promoting abstinence in this population. Future randomized clinical trials are warranted.

Examine incidence and factors associated with loss to follow-up (LTFU) in the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) cohort.ALLRT is a prospective cohort of HIV-infected persons randomized to antiretroviral (ARV) regimens/strategies in ACTG trials and followed long-term after the trial ends. Person-years were calculated from ALLRT entry until loss to follow-up (LTFU; defined using off-study reasons or ≥ 3 consecutive missed visits), death/ severe debilitation/site closures, or June 2009 (censored). Poisson regression was used to examine LTFU factors separately among participants who were ARV naïve or ARV experienced at trial entry.Among 4,630 participants (22,524 person-years), 1,140 were lost to follow-up, 237 died, 29 were severely debilitated, and 443 were at sites that closed. The LTFU incidence was 5.5 and 4.2 per 100 person-years among previously ARV-naïve and ARV-experienced participants, respectively. In both groups, age ≤ 50, site location, being off ARVs, and viral load ≥ 400 copies/mL were associated with a higher risk of LTFU. Among ARV-naïve participants, male sex, education16 years, intravenous drug use, and cigarette smoking were also associated with LTFU.Knowledge of differential LTFU can help researchers identify participants at risk of LTFU in longitudinal HIV cohorts and design retention strategies, thereby limiting study bias. The identified factors should be included in inverse probability of weighting models to account for LTFU.

As mortality due to AIDS-related causes has decreased with the use of antiretroviral therapy, there has been a rise in deaths related to non-AIDS-defining illnesses. Given the exceedingly high prevalence of cigarette smoking among individuals living with HIV infection, tobacco has been implicated as a major contributor to this paradigm shift. Evidence suggests that smoking-related illnesses, such as cardiovascular disease, respiratory illnesses, and certain malignancies, contribute substantially to morbidity and mortality among HIV-infected persons. In this review, we summarize the adverse health consequences of smoking relevant to HIV-infected individuals and discuss smoking cessation in this unique population, including a discussion of barriers to quitting and a review of studies that have examined smoking cessation interventions.

Drug and alcohol use have been associated with a worse prognosis in short-term and cross-sectional analyses of HIV-infected populations, but longitudinal effects on adherence to antiretroviral therapy (ART) and clinical outcomes in advanced AIDS are less well characterized. We assessed self-reported drug and alcohol use in AIDS patients, and examined their association with non-adherence and death or disease progression in a multicenter observational study. We defined non-adherence as reporting missed ART doses in the 48 hours before study visits. The association between drug use and ART non-adherence was evaluated using repeated measures generalized estimating equation (GEE) models. The association between drug and alcohol use and time to new AIDS diagnosis or death was evaluated via Cox regression models, controlling for covariates including ART adherence. Of 643 participants enrolled between 1997 and 1999 and followed through 2007, at entry 39% reported ever using cocaine, 24% amphetamines, and 10% heroin. Ongoing drug use during study follow-up was reported by 9% using cocaine, 4% amphetamines, and 1% heroin. Hard drug (cocaine, amphetamines, or heroin) users had 2.1 times higher odds (p=0.001) of ART non-adherence in GEE models and 2.5 times higher risk (p=0.04) of AIDS progression or death in Cox models. Use of hard drugs was attenuated as a risk factor for AIDS progression or death after controlling for non-adherence during follow-up (HR = 2.11, p=0.08), but was still suggestive of a possible adherence-independent mechanism of harm. This study highlights the need to continuously screen and treat patients for drug use as a part of ongoing HIV care.

OBJECTIVE To evaluate the pharmacokinetics and pharmacogenomics of efavirenz (EFV) and lopinavir/ritonavir (LPV/RTV) in HIV-infected persons requiring hemodialysis. DESIGN Prospective, observational study of HIV-infected hemodialysis patients receiving one 600 mg tablet daily of EFV (N = 13) or three 133.3/33.3 mg capsules twice daily of LPV/RTV (N = 13). METHODS Twenty-four-hour EFV and 12-h LPV/RTV pharmacokinetics were assessed. Geometric mean ratios were calculated using historical controls with normal renal function. The effects of several candidate gene polymorphisms were also explored. RESULTS The geometric mean [95% confidence interval (CI); percentage of coefficient of variation (% CV)] Cmin, Cmax, and area under the curve (AUC) for the EFV group were 1.81 microg/ml (0.93, 3.53; 103%), 5.04 microg/ml (3.48, 7.29; 72%), and 71.5 microg h/ml (43.2, 118.3; 93%), respectively. These parameters were 2.76 microg/ml (1.86, 4.11; 53%), 8.45 microg/ml (6.41, 11.15; 52%), and 69.6 microg h/ml (55.6, 87.2; 37%) for LPV and 0.08 microg/ml (0.05, 0.14; 63%), 0.58 microg/ml (0.44, 0.76; 41%), and 3.74 microg h/ml (2.91, 4.80; 37%) for RTV. The AUC geometric mean ratios (90% CI) for EFV, LPV, and RTV were 132% (89, 197), 81% (67, 97), and 92% (76, 111), respectively. LPV Cmin was lower than expected in the hemodialysis group. Higher EFV concentrations were associated with the CYP2B6 516G>T polymorphism. CONCLUSION The pharmacokinetics of EFV and LPV/RTV in hemodialysis suggests that no dosing adjustments are necessary in treatment-naive patients. As HIV-infected hemodialysis patients are disproportionately black, the increased frequency of the CYP2B6 516G>T polymorphism may lead to higher EFV levels. The potentially lower LPV trough levels in this population suggest that LPV/RTV should be used with caution in protease-inhibitor-experienced patients.

ALLRT is a longitudinal cohort study of HIV-infected subjects prospectively randomized into selected clinical trials for antiretroviral (ARV) treatment-naïve and ARV treatment-experienced individuals conducted by the AIDS Clinical Trials Group (ACTG). We describe the rationale, design, and baseline characteristics of the ALLRT cohort and its potential to address important research questions related to ARV therapy.Standardized visits occur every 16 weeks to evaluate long-term clinical, virologic, and immunologic outcomes associated with ARV treatment.A total of 4,371 subjects enrolled in ALLRT from January 2000 through June 2007. Of these, 3,146 (72%) were ARV naïve at parent study entry (18% female, 44% white, 32% black, 21% Hispanic; median age 37 years, CD4 count 218 cells/microL, follow-up 3.6 years; 343 [11%] followedor = 8 years) and 1,225 (28%) were treatment experienced (13% female, 59% white, 20% black, 17% Hispanic; median age 42 years, CD4 count 325 cells/microL, follow-up 5.7 years).ALLRT provides the opportunity to understand long-term ramifications of therapeutic ARV choices and determine whether these vary by treatment regimen, timing of treatment initiation, or treatment changes over long-term follow-up. Investigations based on uniform data and specimen collection in the context of randomized ARV treatments will be critical to developing more successful long-term therapeutic strategies for HIV treatment.

Supplemental Digital Content is available in the text, The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults. This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B_2 group, N = 64) or 3 (F4/AS01B_3 group, N = 62) doses of F4/AS01B or placebo (control group, N = 64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4+ T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks. At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B_2 and control group (0.073 log10 copies/mL [97.5% confidence interval (CI): −0.088; 0.235]), or F4/AS01B_3 and control group (−0.096 log10 copies/mL [97.5% CI: −0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4+ T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B_2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4+ T-cells, but had no significant impact on F4-specific CD8+ T-cell and anti-F4 antibody levels. F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4+ T-cell responses, but did not reduce HIV-1 VL, impact CD4+ T-cells count, delay ART initiation, or prevent HIV-1 related clinical events.

Introduction HIV can damage neurons leading to cognitive impairment. Epidemiological observations suggest that neuropsychological impairment might progress despite successful HAART therapy, but available prevalence estimates are based on populations that were selected for impairment. Methods Of 433 advanced AIDS patients with documented immune reconstitution (CD4 lymphocyte counts 100 cells/microl after HAART), 286 had brief assessments of cognition (Trailmaking A/B and Digit Symbol Tests) at least once, no confounding neurological conditions, and available neuropsychological norms with comprehensive demographic corrections. At entry, most were immune reconstituted on HAART (median CD4 cell count 230 cells/microl) and HIV was suppressed (65% 20 000 RNA copies/ml). Results Over one quarter (27%) of participants exhibited impairment at their initial neuropsychological assessment, a rate nearly twice that expected in a normal (HIV-uninfected) reference population (14%). These impaired participants did not differ from the unimpaired group with respect to age, sex, education, race, CD4 lymphocyte counts, or HIV-RNA levels. Improved performance on neuropsychological tests was documented over a 2-year period 3-5 years after initiating HAART. This improvement was marginally associated with the continued or improving control of plasma HIV-RNA levels, but not with concurrent levels of immune recovery (CD4 lymphocyte counts). Conclusion Most advanced AIDS patients responding to HAART for prolonged periods have stable or improving cognition, but remain more likely to be impaired than the general population. During HAART, improving test performance probably reflects both practice effects and continuing neurological recovery after more than 3 years of HAART.

Objective. We sought to compare clearance rates of plasma human immunodeficiency virus type 1 (HIV-1) RNA in men and women starting triple-nucleoside-based versus efavirenz (EFV)-based regimens. Methods. First- and second-phase decay rates of plasma HIV-1 were compared in men and women initiating a triple nucleoside reverse-transcriptase inhibitor (NRTI) regimen versus regimens that included EFV plus an NRTI. Subjects (n = 64) were randomized to receive zidovudine/lamivudine/abacavir (triple-nucleoside regimen), zidovudine/lamivudine plus EFV (3-drug EFV regimen) or zidovudine/lamivudine/abacavir plus EFV (4-drug EFV regimen). Plasma HIV-1 RNA levels were fitted to a biexponential viral-dynamics model using a nonlinear mixed-effects model. Nonparametric Wilcoxon tests compared empirical Bayes estimates of first- and second-phase viral decay rates between treatment arms and sex. Results. Median first-phase viral decay rates were significantly faster in subjects receiving the 3-drug EFV regimen (0.67/day), compared with those receiving the triple-nucleoside regimen (0.56/day; P = .02). The second-phase viral decay rate was also faster in the 3-drug EFV group than in the triple-nucleoside group (P = .09). Decay rates in the 4-drug EFV group were intermediate. Viral decay rates were not significantly different in men and women. Conclusions. Faster initial viral decay in subjects randomized to a 3-drug EFV-based regimen corresponded to the overall superior efficacy of that regimen. Viral decay rates did not differ by sex.

OBJECTIVE To evaluate the effects of metformin and rosiglitazone, alone or in combination, on fat distribution, insulin sensitivity, and lipids in HIV-infected patients with insulin resistance and changes in fat distribution. METHODS A total of 105 subjects were randomly assigned to receive metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks) with rosiglitazone placebo (Met/P, N = 26); rosiglitazone (4 mg/day) with metformin placebo (Rosi/P, N = 27); rosiglitazone (4 mg/day) plus metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks; Met/Rosi, N = 25); or dual placebo (P/P, N = 27) for 16 weeks. Efficacy assessments included oral glucose tolerance testing, abdominal computed tomography, whole-body dual-energy X-ray absorptiometry, and the measurement of fasting lipids and other biochemical indices. Safety was monitored throughout. Intent-to-treat analyses were performed using non-parametric methods. RESULTS The median insulin area under the curve (AUC) decreased significantly compared with baseline in both groups randomly assigned to rosiglitazone (Rosi/P -25.7 microIU/ml, P = 0.012; Met/Rosi -17.7 microIU/ml, P = 0.002); and tended to decrease in the Met/P group (-11.1 microIU/ml, P = 0.058). The change in AUC with combination therapy was significant compared with placebo (P = 0.032). No treatment was associated with significant changes in visceral or subcutaneous abdominal fat. Leg fat increased in subjects on Rosi/P compared with placebo (+4.8 versus -8.3%, P = 0.034). Rosiglitazone, but not metformin, increased adiponectin but also increased LDL-cholesterol and decreased HDL-cholesterol. Gastrointestinal effects occurred frequently in subjects on metformin. CONCLUSION Both treatments improved insulin sensitivity, but neither reduced visceral fat. Rosiglitazone may increase subcutaneous fat in some individuals.

OBJECTIVE Nevirapine-based therapy is associated with increased frequency of adverse events among women with CD4+ cell count of 250 cells/microL or greater. We evaluated the safety of nevirapine-based antiretroviral therapy in human immunodeficiency virus (HIV)-1-infected pregnant women. METHODS We retrospectively evaluated 23 pregnancies managed with nevirapine-based regimens from July 2001 to April 2005. The incidence of adverse events was determined and analyzed by CD4+ cell count of either less than or greater than or equal to 250 cells/microL, and gestational age when nevirapine was initiated. Liver function abnormality was graded according to the National Institute of Allergy and Infectious Diseases Division of AIDS toxicity guidelines. RESULTS Five of 23 patients (21.7%) started nevirapine-based therapy after 27 weeks of gestation. All 3 cases of adverse events occurred in this group within 6 weeks of initiating therapy and with CD4+ cell count greater than 250 cells/microL. A significant difference was noted in the proportion of patients who developed toxicity while starting nevirapine in the third trimester (3/5, 60%; 95% confidence interval 14.66-94.73) compared with those starting nevirapine earlier in pregnancy (0/18, 0%; 95% confidence interval 0.0-18.53; P < .006). Two patients developed rash, eosinophilia, and liver function abnormality, with one developing clinical hepatitis and renal failure. A third patient had abnormal elevation of liver enzymes but was asymptomatic. CONCLUSION The incidence of adverse events with nevirapine may be lower than previously reported (13% versus 29%) and may be primarily noted with initiating the drug late in pregnancy. Further study of nevirapine in larger cohorts of HIV-infected pregnant women is warranted to determine the relationship between nevirapine hepatotoxicity and trimester use. LEVEL OF EVIDENCE II-3.

Descriptions of the durability and consequences of immune reconstitution in patients who start highly active antiretroviral therapy (HAART) while severely immunosuppressed are limited.Patients with previous CD4+ cell counts50 cells/mm3, all of whom had HAART-induced increases in CD4+ cell counts of100 cells/mm3 on 2 separate occasions (measured sequentially at least 4 weeks apart), were enrolled in a prospective trial and observed every 16-32 weeks. Evaluations included assessments for new opportunistic complications, virologic (human immunodeficiency virus [HIV] RNA load) and immunologic (CD4+ cell count) responses, or death.The median follow-up duration for 612 subjects was 184 weeks (range, 8-216 weeks). The rate of increase in CD4+ cell counts was approximately 5.9 cells/mm3 every 8 weeks, with the degree of increase associated with the baseline HIV RNA load (500 vs.or =500 copies/mL). Subsequent measurements of virologic suppression based on HIV RNA levels were also associated with predicted CD4+ cell responses. Thirty-three AIDS-defining illnesses were reported (1.75 events per 100 person-years of follow-up);40% (14 cases) occurred with higher than expected CD4+ cell counts.CD4+ cell count increases are related to virological control, with continuing increases seen in individuals who are immunosuppressed. Opportunistic illnesses and/or complications are infrequent but can occur at any time, even in patients who maintained an elevated CD4+ cell count.

The effect of length of therapy on the safety and efficacy profile of continuous intravenous (CIV) interleukin-2 (IL-2) in combination with antiretroviral therapy (ART) was evaluated in 81 HIV-seropositive patients with CD4(+) T-cell counts of 100-300/mm(3). Patients were randomized to CIV IL-2 (12 mIU/day) for 3, 4, or 5 days plus ART every 8 weeks for six cycles, or to ART alone. The mean percent increase in CD4(+) T-cell counts was 24.5% for IL-2 recipients compared with a mean percent decrease of 30.5% for control patients (P = 0.005). Increasing duration of CIV IL-2 therapy resulted in improved CD4(+) T-cell response. The most frequent clinical adverse events and laboratory abnormalities were predominantly of grade 1 or 2 severity. However, grade 3 or 4 events were reported in 57%, 60%, and 84% of the 3-, 4-, and 5-day CIV IL-2 patients, respectively. Serious adverse events, mainly due to the requirement of hospitalization, occurred in 20% of IL-2 recipients, compared with 10% of control patients. Viral load during the course of the study was not different among the treatment groups. IL-2 therapy in cycles of 5 days resulted in an optimal increase in CD4(+) T-cell counts and is the preferred cycle length for IL-2 therapy geared toward increasing CD4(+) T-cell numbers.

Background: In contrast to the immunosupressed patient population, the prevalence of fluconazole-resistant strains of Candida albicans among healthy individuals has not been extensively studied. Methods: Candida species were cultured form 50 healthy outpatients with clinical signs of oral candidiasis. Following one week of the recommended fluconazole regimen, post-treatment cultures were obtained. Both pre- and post-treatment yeasts were identified and in vitro susceptibility testing was performed using the NCCLS M-27A method. Strains were further differentiated using established cDNA probes. Results: Forty-four patients (88%) had positive C.albicans cultures prior to treatment. Antifungal susceptibility testing of these strains demonstrated no in vitro resistance to fluconazole. At post-treatment evaluation, eight patients (18%) had persistent signs of infection and 10 patients (23%) had positive Candida sp. cultures despite no clinical signs of infection. DNA analysis confirmed that the same C. albicans strain was present both in the pre-treatment and the post-treatment cultures. Conclusions: Our results showed that the presence of fluconazole-resistant strains of C.albicans does not appear to be prevalent among healthy outpatients furthermore, in vitro antifungal susceptibility testing does not always predict successful therapy in these patients.

We conducted a multicenter, prospective study of the risk factors, natural history, and outcome of fluconazole-refractory mucosal candidiasis (FRMC) in 832 persons with advanced human immunodeficiency virus (HIV) infection (median CD4 cell count, 14/mm3) during 1994-1996. FRMC was defined as mucosal candidiasis that failed to resolve despite 14 days of therapy with daily doses (> or =200 mg) of fluconazole. Thirty-six persons (4.3%) had FRMC (35, oral; 1, esophageal), for an incidence of 4.2 per 100 person-years (859.7 total years of follow-up). In a multivariate model, the use of trimethoprim-sulfamethoxazole within 6 months of enrollment (relative risk [RR], 2.39; P=.04) and the use of fluconazole daily or every other day (RR, 5.64; P=.004) were significantly associated with the development of FRMC. The median survival after the development of FRMC was 32.6 weeks. In conclusion, the annual incidence of FRMC was

This multicenter, randomized, dose-ranging study was performed to determine the safety and efficacy of two different doses of azithromycin for treating disseminated Mycobacterium avium complex (MAC) in patients with AIDS. Eighty-eight AIDS patients with symptoms and blood cultures consistent with disseminated MAC were treated with 600 or 1,200 mg of azithromycin daily for 6 weeks; 62 patients completed the entire 6 weeks of study. Of note, this study was done prior to the time when combination antiretroviral or anti-MAC regimens were the standard of care. Over the 6-week study period, symptomatic improvement was noted in both dose groups. Microbiological responses were comparable, with mean decreases of 1.5 and 2.0 log CFU/ml in the high- and low-dose groups, respectively. Sterilization of blood cultures occurred in 54% of samples; patients with lower baseline colony counts were more likely to achieve culture negativity. Resistance developed in one patient. Gastrointestinal symptoms were the most common side effects and were more frequent in patients receiving 1,200 mg. Azithromycin is a useful alternative treatment for disseminated MAC infection in AIDS patients. Symptomatic improvement correlates with measurable decreases in mycobacterial load.

© 2014 American College of Physicians. Objective: To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability.Background: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIVinfected persons.Design: A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954) Setting: 57 sites in the United States and Puerto Rico.Patients: Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors.Intervention: Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d.Measurements: Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability.Results: Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as-10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir.Primary Funding Source: National Institute of Allergy and Infectious Diseases.Limitation: The trial was open-label, and ritonavir was not provided.Conclusion: Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen.

PURPOSE: This study assesses the efficacy and safety of fluconazole therapy in patients with acquired immunodeficiency syndrome (AIDS) and mild to moderately severe manifestations of disseminated histoplasmosis. PATIENTS AND METHODS: This was a multicenter, open-label, nonrandomized prospective trial. All patients had AIDS and disseminated histoplasmosis. Patients were treated with 1,200 mg of fluconazole given by mouth once on the first day, then 600 mg once daily for 8 weeks, and those patients who improved clinically were then assigned fluconazole maintenance therapy 200 mg once daily for at least 1 year. Interim analysis revealed a high failure rate (10 of 20, 50%), causing revision of the protocol to increase the fluconazole dose to 1,600 mg given once on the first day, then 800 mg once daily, and the duration to 12 weeks for induction therapy and then 400 mg daily for 1 year for maintenance therapy. MEASUREMENTS AND MAIN RESULTS: Thirty-six of 49 patients (74%; 95% confidence interval [CI]: 59% to 85%) with mild to moderately severe clinical manifestations who entered into the revised study responded to 800 mg of fluconazole daily for 12 weeks as induction therapy. Of the seven patients who failed induction therapy because of progression of histoplasmosis, one died of the infection. Of 36 patients who entered into the maintenance phase of the study receiving 400 mg of fluconazole daily for 1 year, 11 (30.5%) relapsed, including one who died (2.8%). Two of the 49 patients (4.1%) were removed because of grade 4 adverse events, alkaline phosphatase elevation for one and aspartate aminotransferase elevation in the other. The relapse-free rate at 1 year was 53% (95% CI: 32% to 89%), prompting closure of the study. CONCLUSIONS: Fluconazole 800 mg daily is a safe and moderately effective induction therapy for mild or moderately severe disseminated histoplasmosis in patients with AIDS. On the basis of historic comparison, fluconazole 400 mg daily is less effective than itraconazole 200 to 400 mg daily or amphotericin B 50 mg given weekly as maintenance therapy to prevent relapse.

The treatment of disease caused by Mycobacterium avium complex (MAC) in HIV-infected individuals has undergone considerable evolution over the past 15 years. Agents with known antimycobacterial activity such as rifampin/rifabutin, ethambutol, and clofazimine, as well as others such as amikacin, liposome-encapsulated gentamicin, several of the fluoroquinolones (ciprofloxacin, ofloxacin, and sparfloxacin), and the new macrolides, azithromycin and clarithromycin, have all been used with varying degrees of success. Of all these agents, the macrolides have clearly had the biggest impact to date on the management of disseminated MAC. Studies of both azithromycin and clarithromycin in short-term monotherapy trials have corroborated their clinical and microbiological efficacy. The risk of drug resistance with monotherapy, however, has prompted investigation of combination regimens for the treatment of MAC. A recent study of a three-drug, clarithromycin-based regimen versus a four-drug regimen without clarithromycin has shown that patients treated with the regimen containing clarithromycin had significantly greater overall symptomatic improvement, more rapid and significant clearing of mycobacteremia, and improved survival. Results from studies of combination regimens with azithromycin should be available soon. Although there is still no "regimen of choice," initial treatment with at least two active agents, one of which should be either azithromycin or clarithromycin, is the currently recommended approach; the majority opinion favors ethambutol as the preferred second agent. Use of adjunctive therapies and more potent antiretroviral regimens may also play a role.

We assessed laboratory monitoring after combination antiretroviral therapy initiation among 3678 patients in a large US multisite clinical cohort, censoring participants at last clinic visit, combination antiretroviral therapy change, or 3 years. Median days (interquartile range) to first hematologic, hepatic, renal, and lipid tests were 30 (18-53), 31 (19-56), 33 (20-59), and 350 (96-1106), respectively. At 1 year, approximately 80% received more than 2 hematologic, hepatic, and renal tests consistent with guidelines. However, only 40% received 1 or more lipid tests. Monitoring was more frequent in specific subgroups, likely reflecting better clinic attendance or clinician perception of higher susceptibility to toxicities.

Background Cryptococcal meningitis and other serious fungal infections are common complications in patients infected with the human immunodeficiency virus (HIV). Fluconazole is effective for long-term suppression of many fungal infections, but its effectiveness as primary prophylaxis had not been adequately evaluated. Methods We conducted a prospective, randomized trial that compared fluconazole (200 mg per day) with clotrimazole troches (10 mg taken five times daily) in patients who were also participating in a randomized trial of primary prophylaxis for Pneumocystis carinii pneumonia. Results After a median follow-up of 35 months, invasive fungal infections had developed in 4.1 percent of the patients in the fluconazole group (9 of 217) and in 10.9 percent of those in the clotrimazole group (23 of 211; relative hazard, as adjusted for the CD4+ count, 3.3; 95 percent confidence interval, 1.5 to 7.6). Of the 32 invasive fungal infections, 17 were cryptococcosis (2 in the fluconazole group and 15 in the cl...

Summary Objective To evaluate whether asthma and airway hyper-responsiveness are associated with HIV infection. Methods We reviewed the literature on HIV-associated pulmonary diseases, pulmonary symptoms, and immune changes which may play a role in asthma. The information was analyzed comparing the pre-HAART era to the post-HAART era data. Results HIV-seropositive individuals commonly experience respiratory complaints yet it is unclear if the frequency of these complaints have changed with the initiation of HAART. Changes in pulmonary function testing and serum IgE are seen with HIV infection even in the post-HAART era. An increased prevalence of asthma among HIV-seropositive children treated with HAART has been reported. Conclusion The spectrum of HIV-associated pulmonary disease has changed with the introduction of HAART. Current data is limited to determine if asthma and airway hyper-responsiveness are more common among HIV-seropositive individuals treated with HAART.

Recommended first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection includes the use of two nucleoside or nucleotide reverse-transcriptase inhibitors (NRTIs) combined with one or more agents from other antiretroviral drug classes (nonnucleoside reverse-transcriptase inhibitors [NNRTIs], protease inhibitors [PIs], or integrase inhibitors) [1, 2]. Lifelong treatment is required to maintain HIV suppression, improve immune function, and minimize morbidity and mortality associated with HIV disease progression. Therefore, understanding long-term risks associated with ART is paramount. The observational Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) cohort reported that current or recent use of abacavir was associated with increased risk of myocardial infarction (MI) [3]; data from other cohort studies and clinical trials of abacavir have provided conflicting results [4–11]. For example, although analyses of the Strategies for Management of Antiretroviral Therapy (SMART) study found more than a 4-fold increase in risk [4], a GlaxoSmithKline meta-analysis of randomized trials found no increased risk [5] and an association detected in the French Agence Nationale de Recherches sur le SIDA (ANRS) cohort was not apparent after cocaine and intravenous drug users were excluded from the analysis cohort [10]. These differences may be explained by confounding and population differences, as well as differences in analytical approach. Because abacavir was considered an attractive ART for subjects with cardiovascular disease (CVD) risk [6,12–14], confounding is particularly problematic [15–17]. Recent treatment guidelines now caution against the use of abacavir in subjects with high CVD risk [1, 2], which will further confound analyses addressing this issue. Previous analyses have focused on the increased relative risk of MI associated with abacavir. When an event is rare—as is MI in this context—even very large relative risks may have limited population-level relevance, making estimation of absolute risk difference essential. We ascertained population level CVD risk associated with initiating ART with abacavir-containing regimens using a cohort of ART-naive persons randomly assigned ART through prospective clinical trials. Our unique cohort provides a means to address confounding and channeling bias issues of traditional observational cohorts. Our analytical approach and estimation of absolute risk places the CVD risk associated with abacavir for the treatment of ART-naive populations into a broader clinical context.

Background: Prospective data on factors associated with the non-AIDS-defining cancer (NADC) incidence in HIV-infected individuals are limited. Methods: We examined the NADC incidence in 3,158 antiretroviral treatment (ART)-naïve subjects after ART initiation in AIDS Clinical Trials Group trials; extended follow-up was available for 2,122 subjects. Poisson regression was used to examine the associations between covariates and incident NADC. Results: At ART initiation, subjects (median age 37 years) were 40% non-Hispanic whites, and 82% were male; 23% had CD4+ T cell count ≤50 cells/mm3 and 25% had CD4 >350 cells/mm3. Median follow-up was 3.8 years. Among 64 incident NADCs, the most common were 8 anal cancers, 8 basal cell carcinomas, 8 Hodgkin’s disease, and 6 lung cancers. In univariate models, age, smoking and recent (time-updated) CD4 were associated with incident NADC. There was no association between initial ART drug class (protease inhibitor, nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor) and NADC. After adjusting for age, race and sex: smoking [relative risk = 2.12 (95% CI = 1.1–4.08)] and recent CD4 (≤50 cells/mm3: 3.58, 1.22–10.45; 51–200 cells/mm3: 2.54, 1.30–5.0; 201–350 cells/mm3: 2.37, 1.32–4.26 vs. >350 cells/mm3) were associated with NADC. Conclusion: Smoking and lower recent CD4 levels, but not initial ART drug class, were associated with NADC. Strategies for maintaining higher CD4 cell counts and successful smoking cessation may reduce the NADC incidence in the HIV-infected population.

Background: AIDS-defining events (ADEs) decreased in the era of highly active antiretroviral therapy but still lead to hospitalizations and deaths. Understanding factors related to ADEs is important to mitigate events. Methods: We examined the relationship between demographics, behaviors, comorbidities, laboratory, clinical measurements, and ADEs diagnosed among subjects randomized to antiretroviral treatments (ART)/strategies and followed prospectively. Logistic regression models using generalized estimating equations generated odds ratios (ORs) focusing on the relationship between current CD4 + T-cell count (CD4)/HIV-1 RNA viral load (VL) and ADEs in the subsequent 16-week study period. Results: Among the 2948 subjects in the analysis, overall incidence of ADEs was 1.53 per 100 person-years. Multivariate regression models adjusted for demographics, body mass index, and ADE history. A 6-level time-varying variable examined VL (> 100,000 copies/mL, ≤100,000) at CD4 levels (0-50, 51-200, >200 cells/μL); reference level was CD4 >200/VL ≤100,000. Among ART naives, odds of having an ADE in the subsequent 16-week interval were greater among subjects with lower CD4 counts; this relationship was modified by VL level (CD4 ≤50/VL > 100,000: OR 37.2; CD4 ≤50/VL ≤100,000: OR 30.5; CD4 51-200/VL > 100,000: OR 13.0; CD4 51-200/VL ≤100,000: OR 4.5; all P values

The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known.In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily antiretroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA levelor = 1000 copies per milliliter at or after 16 weeks and before 24 weeks, oror = 200 copies per milliliter at or after 24 weeks).A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48.In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.)

BACKGROUND Ezetimibe inhibits intestinal absorption of cholesterol. METHODS Multicentered double-blind, randomized, placebo-controlled, crossover study to determine the short-term safety, efficacy, and tolerability of ezetimibe in combination with ongoing statin therapy in HIV-infected adults with elevated low-density lipoprotein cholesterol (LDL-C). Participants on stable HAART with fasting LDL-C at least 130 mg/dl and stable statin were randomized to ezetimibe 10 mg daily or placebo for 12 weeks followed by 4 weeks of washout and then 12 weeks with alternative study assignment. Percentage and absolute change in LDL-C (primary endpoint), total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, and high sensitivity C-reactive protein were compared. Changes in clinical symptoms and safety laboratory measurements were assessed. RESULTS Forty-four participants enrolled: 70% men, median age 49 years, 43% White/Non-Hispanic, median CD4 cell count 547 cells/microl, and 95% HIV RNA less than 50 copies/ml. Median (interquartile range) percentage change in LDL-C was -20.8% (-25.4, -10.7) with ezetimibe and -0.7% (-10.3,18.6) with placebo; the median within-participant effect of ezetimibe was -14.1% (-33.0, -5.0; P < 0.0001). Median difference in absolute LDL-C values between ezetimibe and placebo was -32 mg/dl (-58, -6, P < 0.0001). Significant differences in within-participant effect of ezetimibe were noted for total cholesterol -18.60% (-27.22, -11.67, P < 0.001), non-HDL-C -23.18% (-33.14, -14.36, P < 0.0001), and apolipoprotein B -8.73% (-18.75, 1.99, P = 0.02). No significant changes seen in HDL-C, triglyceride, or high sensitivity C-reactive protein. Ezetimibe was well tolerated. Adverse events were similar between phases. CONCLUSION The present short-term study found adding ezetimibe to ongoing statin therapy was well tolerated and effective in reducing LDL-C, total cholesterol, non-HDL-C, and apolipoprotein B. Adding ezetimibe to statin therapy offers reasonable treatment option for HIV-infected patients with elevated LDL-C.