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Context Exaggerated postprandial incretin and insulin responses are well documented in postbariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG). Objective We sought to compare meal-stimulated hormonal response in those with PBH after SG vs RYGB. Methods We enrolled 23 post-SG (12 with and 11 without PBH) and 20 post-RYGB (7 with and 13 without PBH) individuals who underwent bariatric surgery at our institution. PBH was defined as plasma glucose less than 60 mg/dL on 4-hour mixed-meal tolerance test (MTT). Islet and incretin hormones were compared across the 4 groups. Results Participants (N = 43) were on average 5 years post surgery, with a mean age of 48 years, mean preoperative body mass index of 48.4, 81% female, 61% White, and 53% post SG. Regardless of PBH, the SG group showed lower glucose, glucagon, and glucagon-like peptide 1 (GLP-1) responses to MTT and similar insulin and glucose-dependent insulinotropic polypeptide (GIP) responses compared to the RYGB group. Among those with PBH, the SG group following the MTT showed a lower peak glucose (P = .02), a similar peak insulin (90.3 mU/L vs 171mU/L; P = .18), lower glucagon (P Conclusion Among individuals with PBH, those who underwent SG were significantly different compared to RYGB in meal-stimulated hormonal responses, including lower glucagon and GLP-1 responses, but similar insulin and GIP responses. Future studies are needed to better understand the differential contribution of insulin and non–insulin-mediated mechanisms behind PBH after SG vs RYGB.

OBJECTIVES: People with HIV (PWH) are at increased risk for premature cardiovascular disease (CVD). Clonal hematopoiesis is a common age-related condition that may be associated with increased CVD risk. The goal of this study was to determine the prevalence of clonal hematopoiesis and its association with chronic inflammation and CVD in PWH. DESIGN: Cross-sectional study utilizing archived specimens and data from 118 men (86 PWH and 32 HIV-uninfected) from the Baltimore-Washington DC center of the Multicenter AIDS Cohort Study (MACS) who had had coronary computed tomography angiography (CTA) and measurement of 34 serologic inflammatory biomarkers. METHODS: Clonal hematopoiesis was assessed on peripheral blood mononuclear cells utilizing targeted error-corrected next generation sequencing (NGS) focused on 92 genes frequently mutated in hematologic malignancies. Clinical and laboratory data were obtained from the MACS database. RESULTS: Clonal hematopoiesis with a variant allele frequency (VAF) greater than 1% was significantly more common in PWH [20/86 (23.3%)] than in HIV-uninfected men [2/32 (6.3%)] (P = 0.035). PWH with clonal hematopoiesis (VAF > 1%) were more likely to have coronary artery stenosis of at least 50% than those without clonal hematopoiesis [6/20 (30%) vs. 6/64 (9%); P = 0.021]. Presence of clonal hematopoiesis was not significantly associated with serological inflammatory markers, except for significantly lower serum leptin levels; this was not significant after adjustment for abdominal or thigh subcutaneous fat area. CONCLUSION: Clonal hematopoiesis was more common in PWH and among PWH was associated with the extent of coronary artery disease. Larger studies are needed to further examine the biological and clinical consequences of clonal hematopoiesis in PWH.

BACKGROUND The longer-term risks of statins on physical function among people with HIV are unclear. METHODS Longitudinal analysis of Multicenter AIDS Cohort Study men between 40 and 75 years of age with ≥2 measures of gait speed or grip strength. Generalized estimating equations with interaction terms between (1) statin use and age and (2) HIV serostatus, age, and statin use were considered to evaluate associations between statin use and physical function. Models were adjusted for demographics and cardiovascular risk factors. RESULTS Among 2021 men (1048 with HIV), baseline median age was 52 (interquartile range 46-58) years; 636 were consistent, 398 intermittent, and 987 never statin users. There was a significant interaction between age, statin, and HIV serostatus for gait speed. Among people with HIV, for every 5-year age increase, gait speed (m/s) decline was marginally greater among consistent versus never statin users {-0.008 [95% confidence interval (CI) -0.017 to -0.00007]; P = 0.048}, with more notable differences between intermittent and never users [-0.017 (95% CI -0.027 to -0.008); P < 0.001]. Similar results were observed among men without HIV. Significant differences in grip strength (kg) decline were seen between intermittent and never users [-0.53 (95% CI -0.98 to -0.07); P = 0.024] and differences between consistent and never users [-0.28 (95% CI -0.63 to 0.06); P = 0.11] were not statistically significant. CONCLUSIONS Among men with and without HIV, intermittent statin users had more pronounced declines in physical function compared with consistent and never users. Consistent statin use does not seem to have a major impact on physical function in men with or without HIV.

Background Diabetes mellitus is a prevalent condition among hospitalized patients and the inpatient setting presents an opportunity for providers to review and adjust antihyperglycemic medications. We sought to describe practice patterns and predictors of antihyperglycemic intensification (AHI) at hospital discharge for type 2 diabetes mellitus (T2DM) patients not on home insulin. Methods We conducted a retrospective study of adult patients with T2DM receiving either non-insulin antihyperglycemic (NIA) or no antihyperglycemic medications prior to admission who were hospitalized within two hospitals in the Johns Hopkins Health System from December 2015 to September 2016. Mean hospital glucose values and observed vs. individualized target hemoglobin A1C values (based on risk of mortality score) were used to define an indication for AHI. Multivariable logistic regression was used to identify predictors of AHI. Results A total of 554 discharges of 475 unique patients were included. An indication for AHI was present in 104 (18.8%) of discharges, and AHI occurred in 30 (28.8%) of these discharges. Higher mean admission BG values and A1C, fewer pre-admission antihyperglycemic agents, involvement of the diabetes service, and admitting service were associated with AHI, while no association was observed with age, sex, race, risk of mortality and severity of illness scores, or length of stay. AHI was not associated with 30-day readmission. Conclusion An indication for AHI occurs relatively infrequently among hospitalized patients, but when present, AHI occurs in approximately 1 in 3 discharges. AHI appears to be related largely to the degree of hyperglycemia, and diabetes service involvement. Further studies are needed to understand the implications of AHI at hospital discharge on short and long-term outcomes in this population.

AIM: We investigated the association between acculturation strategies and cardiometabolic risk among South Asian(SA) immigrants in the US. METHODS: In this cross-sectional analysis of data from 849 SA participants in the Mediators of Atherosclerosis in SAs Living in America (MASALA), we performed multidimensional measures of acculturation to categorize the participants into three acculturation classes: separation(preference for SA culture), assimilation(preference for US culture), and integration(similar preference for both cultures). Differences in glycemic indices, blood pressure, lipid parameters and body composition by acculturation strategy were examined. RESULTS: Women in the integration class had the lowest prevalence of diabetes (16.4%), prediabetes (29.7%), fasting and 2-hr glucose compared to women in the separation class with the highest prevalence of diabetes (29.3%), prediabetes (31.5%), fasting and 2-hr glucose and 2-hr insulin (all p

OBJECTIVE This study evaluated the association between hemoglobin A1c (A1C) and wound outcomes in patients with diabetic foot ulcers (DFUs). RESEARCH DESIGN AND METHODS We conducted a retrospective analysis of an ongoing prospective, clinic-based study of patients with DFUs treated at an academic institution during a 4.7-year period. Data from 270 participants and 584 wounds were included in the analysis. Cox proportional hazards regression was used to assess the incidence of wound healing at any follow-up time in relation to categories of baseline A1C and the incidence of long-term (≥90 days) wound healing in relation to tertiles of nadir A1C change and mean A1C change from baseline, adjusted for potential confounders. RESULTS Baseline A1C was not associated with wound healing in univariate or fully adjusted models. Compared with a nadir A1C change from baseline of −0.29 to 0.0 (tertile 2), a nadir A1C change of 0.09 to 2.4 (tertile 3) was positively associated with long-term wound healing in the subset of participants with baseline A1C CONCLUSIONS There does not appear to be a clinically meaningful association between baseline or prospective A1C and wound healing in patients with DFUs. The paradoxical finding of accelerated wound healing and increase in A1C in participants with better baseline glycemic control requires confirmation in further studies.

BACKGROUND: Both aging and treated human immunodeficiency virus (HIV)-infected populations exhibit low-level chronic immune activation of unknown etiology, which correlates with morbidity and mortality. Cytomegalovirus (CMV) infection is common in both populations, but its relation to immune activation is unknown. METHODS: T cells from men who have sex with men (22 virologically suppressed HIV(+), 20 HIV(−)) were stimulated with peptides spanning 19 CMV open reading frames, and intracellular cytokine responses were assessed. Soluble and cellular inflammatory markers were assessed by multiplex electrochemiluminescence and flow cytometry, respectively. Frailty was assessed by the Fried criteria. RESULTS: All men had responses to CMV. Proportions of CMV-responsive T cells correlated strongly (r ≥ 0.6 or ≤ −0.6; P < .05) with immunologic markers, depending on donor HIV and frailty status. Markers significantly correlated in some groups after adjustment for multiple comparisons included interferon-γ, tumor necrosis factor-α, interleukin-6, and several chemokines in serum, and the proportion of activated T cells. The magnitude of the CD4 IL-2 response significantly predicted onset of frailty in HIV(−) nonfrail men, but not in HIV(+) nonfrail men. CONCLUSIONS: T-cell responses to CMV may strongly influence chronic immune activation in HIV-uninfected and virologically suppressed HIV-infected men, and may predict frailty in HIV-uninfected men.

Background: Cardiovascular disease (CVD) is more common in people living with HIV (PLWH) and may be related to abnormal immune activation. With aging, the expansion of mutated hematopoietic clones or clonal hematopoiesis (CH) has been associated with CVD events in the general population and is hypothesized to be driven by systemic inflammation. We investigated whether CH was more common in PLWH compared to those without HIV, whether the distribution of CH mutations differed by HIV status, and whether CH was associated with subclinical coronary atherosclerosis in PLWH. Methods: Study participants were selected from men in the Baltimore -Washington DC center of the Multicenter AIDS Cohort Study (MACS) who had had coronary CT angiography (CTA) as part of the MACS Cardiovascular Study 2. The MACS is a prospective study of the natural history of HIV infection in men who have sex with men, and includes both PLWH and HIV-uninfected men. Since the prevalence of CH increases with age, the oldest participants were preferentially included in this study. To detect CH, DNA extracted from viably frozen peripheral blood mononuclear cells or cell pellets was subjected to targeted, error-corrected, ultra-deep next generation sequencing (NGS) which included 70 genes frequently mutated in hematologic malignancies. CTA results and inflammatory biomarker levels were already available from MACS data. Results: The current analysis was a cross-sectional study involving 118 participants: 86 (72.9%) PLWH and 32 (27.1%) HIV-uninfected men (HIV-). The groups were well-balanced in terms of known major risk factors for CH such as age and smoking. The median age was 53 and 54 years for PLWH and HIV- men, respectively (p=0.147). Caucasians represented 37 (43.0%) of PLWH and 21 (65.6%) of HIV- men. Out of 86 PLWH, 72 (83.7%) were on antiretroviral therapy (ART) at the time of the assessment; 41 (47.7%) on a PI-containing regimen and 31 (36.0%) on an NNRTI-containing regimen. The HIV viral load was under 400 copies/mL in 77 (89.5%) of PLWH, and the median (IQR) CD4+ count was 585 (397, 745)/mL. The prevalence of coronary artery stenosis of 50% or more was 12 (14.3%) in PLWH and 5 (16.1%) in HIV- men (p = 0.774). Since the minimum size of the biologically relevant CH is unknown, we applied variant allele frequency (VAF) cut-offs of > 0.5% and > 1%. For both cutoffs, CH was significantly more frequent in PLWH than in HIV- men (p=0.012 and p=0.036, respectively) (Figure 1A). Mutations in epigenetic modifiers (DNMT3A, TET2) were the most common mutations among both PLWH and HIV- men. Interestingly, DNMT3A mutations were more frequent in PLWH (Figure 1B). For both VAF cut-offs, PLWH had significantly more somatic mutations than HIV-uninfected men (p = 0.043 and 0.033, respectively) (Figure 1C). Since inflammation-mediated complications of CH become more apparent in people with larger clones, we focused on CH with VAF > 1% in order to determine the clinical consequences of CH in PLWH. As CH is known to be a risk factor for accelerated CVD in the general population, we asked whether CH was also associated with subclinical atherosclerosis in PLWH. Coronary artery stenosis > 50% (moderate/severe) was significantly more frequent in PLWH with CH compared to PLWH without CH (p = 0.032) (Figure 1 D). This difference remained significant in multivariable logistic regression models that adjusted for the Framingham coronary heart disease 10-year risk (p=0.017) and for the Framingham hard coronary heart disease 10-year risk (p Additionally, we examined the association of serum concentrations of several inflammatory markers such as CRP, IL-1b, IL-6, as well as white blood cell count, with the presence of CH in PLWH, but we found no significant associations. Conclusions: CH was more common in PLWH compared to HIV-uninfected men, and PLWH had more somatic mutations. Moreover, the presence of CH was significantly associated with the presence of coronary artery stenosis > 50% (moderate/severe) in PLWH, even after adjusting for known CVD risk factors. The results from our exploratory analysis may provide a potential explanation for increased CVD in PLWH. Larger studies are warranted to further delineate the etiology of increased CH in PLWH and its impact on accelerated CVD. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

AIMS: We examined whether problem-solving and diabetes self-management behaviors differ by depression diagnosis - major depressive disorder (MDD) and minor depressive disorder (MinDD) - in adults with Type 2 diabetes (T2DM). METHODS: We screened a clinical sample of 702 adults with T2DM for depression, identified 52 positive and a sample of 51 negative individuals, and performed a structured diagnostic psychiatric interview. MDD (n = 24), MinDD (n = 17), and no depression (n = 62) were diagnosed using Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) Text Revised criteria. Health Problem-Solving Scale (HPSS) and Summary of Diabetes Self-Care Activities (SDSCA) questionnaires determined problem-solving and T2DM self-management skills, respectively. We compared HPSS and SDSCA scores by depression diagnosis, adjusting for age, sex, race, and diabetes duration, using linear regression. RESULTS: Total HPSS scores for MDD (β = −4.38; p < 0.001) and MinDD (β = −2.77; p < 0.01) were lower than no depression. Total SDSCA score for MDD (β = −10.1; p < 0.01) was lower than for no depression, and was partially explained by total HPSS. CONCLUSION: MinDD and MDD individuals with T2DM have impaired problem-solving ability. MDD individuals had impaired diabetes self-management, partially explained by impaired problem-solving. Future studies should assess problem-solving therapy to treat T2DM and MinDD and integrated problem-solving with diabetes self-management for those with T2DM and MDD.

Objective: Diabetes is prevalent among hospitalized patients and there are multiple challenges to attaining glycemic control in the hospital setting. We sought to develop an inpatient glycemic management curriculum with stakeholder input and to evaluate the effectiveness of this educational program on glycemic control in hospitalized patients. Methods: Using the Six-Step Approach of Kern to Curriculum Development for Medical Education, we developed and implemented an educational curriculum for inpatient glycemic management targeted to internal medicine residents and hospitalists. We surveyed physicians (n = 73) and conducted focus group sessions (n = 18 physicians) to solicit input regarding educational deficits and desired format of the educational intervention. Based on feedback from the surveys and focus groups, we developed educational goals and objectives and a case-based curriculum, which was delivered over a 1-year period via in-person teaching sessions by 2 experienced diabetes physicians at 3 hospitals. Rates of hypoglycemia and hyperglycemia were evaluated among at-risk patient days using an interrupted time-series design. Results: We developed a mnemonic-based (SIGNAL) curriculum consisting of 10 modules, which covers key concepts of inpatient glycemic management and provides an approach to daily glycemic management: S = steroids, I = insulin, G = glucose, N = nutritional status, A = added dextrose, and L = labs. Following implementation of the curriculum, there was no difference in the rates of hyperglycemia in insulin-treated patients following the intervention; however, there was an increase in the rates of hypoglycemia defined as blood glucose (BG) ⩽ 70 mg/dL (5.6% vs 3.0%, P Conclusions: In this pilot study, a physician-targeted educational curriculum was not associated with improved glycemic control. Adapting the intervention to increase penetration and integrating the curriculum into existing clinical decision support tools may improve the effectiveness of the educational program on glycemic outcomes.

Background: Hospitalized patients with diabetes are at risk of complications and longer length of stay (LOS). Inpatient Diabetes Management Services (IDMS) are known to be beneficial; however, their impact on patient care measures in community, non-teaching hospitals, is unknown. Objectives: To evaluate whether co-managing patients with diabetes by the IDMS team reduces LOS and 30-day readmission rate (30DR). Methods: This retrospective quality improvement cohort study analyzed LOS and 30DR among patients with diabetes admitted to a community hospital. The IDMS medical team consisted of an endocrinologist, nurse practitioner, and diabetes educator. The comparison group consisted of hospitalized patients with diabetes under standard care of attending physicians (mostly internal medicine-trained hospitalists). The relationship between study groups and outcome variables was assessed using Generalized Estimating Equation models. Results: 4,654 patients with diabetes (70.8 ± 0.2 years old) were admitted between January 2016 and May 2017. The IDMS team co-managed 18.3% of patients, mostly with higher severity of illness scores (p

Background: Immigration and the process of acculturation can lead to behavioral changes that exacerbate or reduce diabetes development. We investigated the association between acculturation strategies and cardiometabolic risk (CMR) factors among South Asian (SA) immigrants living in the U.S. Methods: Participants (n=849) in the Mediators of Atherosclerosis in SA Living in America (MASALA) study were categorized into 3 acculturation strategy classes based on self-reported questionnaire responses: separation (preference for SA culture), assimilation (preference for U.S. culture), and integration (similar preference for SA and U.S. cultures). Adjusted linear regression models examined associations of acculturation strategies with fasting and 2 hour glucose, lipids, blood pressure, waist circumference (WC), and body composition. Results: Overall, 22.4, 19.6, and 58% of men and 23.7, 26.2, and 50.1% of women were in separation, assimilation, and integration classes; respectively. Participants in the assimilation class had significantly lower levels of obesity, 2 hour glucose, insulin, HOMA-IR, triglycerides (TG), visceral fat, and higher HDL than those in the separation class (all p Conclusion: SA women who employed an assimilation strategy had a more favorable CMR profile compared to women using a separation strategy. Future research should investigate the behavioral pathways linking acculturation strategies with CMR and potential incorporation into prevention interventions. Disclosure M. Al-Sofiani: None. S.J. Langan: None. A.M. Kanaya: None. N.R. Kandula: None. B. Needham: None. C. Kim: None. D.M. Becker: None. D. Vaidya: None. S. Golden: None. C. Lee: None. R. Rastogi Kalyani: None.

Increasing evidence suggests that chronic cytomegalovirus (CMV) infection significantly impacts T-cell immunity in human immunodeficiency virus (HIV) infection and aging [1–3]. Most of this evidence consists of analysis of T cells specific to epitopes derived from pp65 (encoded by region UL83 in the CMV genome) and immediate early antigen 1 (IE-1; encoded by region UL123). CD8+ T cells directed against these antigens are clonally expanded, as measured through class I tetramers or pentamers in individuals expressing HLA-A2 [2–5], and expansion of CD4+ and CD8+ T cells responsive to these antigens has also been demonstrated by intracellular cytokine staining [6, 7]. In fact, CMV-specific T cells can occupy a very large proportion (up to 30% in some cases) of the circulating T-cell pool in HIV-seronegative persons [8, 9]. However, because human CMV is a large virus with a 230-kb genome and >213 open reading frames (ORFs), it may have a large number of T-cell epitopes, and its overall effect on T-cell immunity is unlikely to be reflected by immune reactivity to just pp65 and IE-1. Indeed, Sylwester et al, in a comprehensive analysis of CMV-specific CD4+ and CD8+ T cells in healthy adults aged 19–55 years, found responses to approximately 150 CMV ORFs [9]. In that study, to accurately predict the total CD8+ T-cell response to CMV, measurement of reactivity to 15 specific ORFs was required; for CD4+ T cells this number was 6, including 2 ORFs that overlapped with those for the CD8+ T-cell response, giving a total of 19. CMV infection is common in people infected with HIV, leading to expansion of CMV-specific T cells in the context of already impaired immunity. For example, Naeger et al reported that, compared with HIV-negative persons, HIV-infected individuals, even those receiving long-term highly active antiretroviral therapy, had significantly higher proportions of CD8+ T cells and, to a lesser extent, CD4+ T cells responding to UL83 and UL123 peptide pools [7]. On the basis of these data, we hypothesized that T-cell responses to pp65 and IE-1 would underestimate the overall T-cell reactivity to CMV in CMV-HIV–coinfected people. Addressing this hypothesis is important for a more accurate understanding of overall T-cell immunity against CMV among HIV-infected and HIV-negative men who have sex with men (MSM), for the design of CMV-based vaccine vectors and for studies relating the immune response against CMV to the aging process, as well as other clinical outcomes. Therefore, we investigated, in both HIV-infected and HIV-negative MSM, the relationship between T-cell responses to UL83 and UL123 peptide pools and those to the remaining 17 CMV ORF peptide pools (Supplementary Table 1 [9]) that accurately predicted the total anti-CMV CD4+ and CD8+ T-cell responses in the study by Sylwester et al described above.

Objective To estimate the crude prevalence of minor depressive disorder (MinD) in a clinic-based population of adults with type 2 diabetes. Methods We screened a clinical sample of 702 adults with type 2 diabetes for depressive symptoms using the Patient Health Questionnaire-2 and performed a structured diagnostic psychiatric interview on 52 screen-positive and a convenience sample of 51 screen-negative individuals. Depressive disorder diagnoses were made using Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) Text Revised criteria and categorized as MinD, major depressive disorder (MDD), or no depressive disorder. We estimated prevalence of MinD and MDD and derived 95% CIs. Results The crude prevalence of current, past, and current or past MinD was 4.3% (95% CI: 0.9–9.2%), 9.6% (95% CI: 3.9–15.9%), and 13.9% (95% CI: 7.7–21.2%), respectively. The crude prevalence of current, past, and current or past MDD was slightly higher—5.0% (95% CI: 1.9–9.4%), 12.0% (95% CI: 6.1–19.5%), and 17.0% (95% CI: 10.1–24.8%), respectively. There was a high prevalence of coexisting anxiety disorders in individuals with MinD (42.2%) and MDD (8.1%). Hemoglobin A1c levels were not significantly different in individuals with MinD or MDD compared to those without a depressive disorder. Conclusions MinD is comparably prevalent to MDD in patients with type 2 diabetes; both disorders are associated with concomitant anxiety disorders. MinD is not included in the DSM-5; however, our data support continuing to examine patients with chronic medical conditions for MinD.

We studied viral evolution in five human leukocyte antigen (HLA)-B*57 patients recently infected with HIV-1. Escape mutations in HLA-B*57-restricted Gag epitopes were present at study entry in all patients, but were not associated with significant increases in viremia. Conversely, no new escape mutations in HLA-B*57-restricted epitopes or known compensatory mutations were detected in patients who experienced significant increases in viremia. Thus, the development of escape mutations alone does not determine virologic outcome in recently infected HLA-B*57 patients.

Interleukin (IL)-2 has been studied as a treatment for HIV infection because it stimulates the proliferation of T cells and augments antiviral immune functions [1,2]. Two regimens have been used: intermittent IL-2 (5 days every 8 weeks, usually 4.5–9 million international units (mIU)/day) and ultra-low-dose (ULD) IL-2 (1.2 mIU/m2/day), which can be given daily for weeks or months [1]. In patients with chronic and early/acute HIV infection, neither regimen has conferred any health benefit when given with concurrent antiretroviral therapy (ART) [3–7], and in patients with chronic HIV infection, ULD IL-2 did not improve viral control after stopping ART [8]. However, treatment of acute/early HIV infection with daily ULD IL-2 and interruption of ART has not been studied. We treated one patient who had taken ART since 1 month after HIV seroconversion with daily ULD IL-2. After receiving IL-2, this patient’s viral load set point off highly active antiretroviral therapy (HAART) was less than 50 copies/ml as compared with 39 000 copies/ml when ART was stopped without IL-2. Further, after IL-2 was stopped, viral load did not rebound for 14 months without ART. A 29-year-old man tested HIV-positive by ELISA and western blot 1.5 months after a negative ELISA, and was treated 30 days later with zidovudine, lamivudine, and efavirenz. Viral load was undetectable for 4 years on ART (with minor changes in regimen), except for occasional blips (all

Suppressed IL-12 production and maladaptive immune activation, both of which are ameliorated by successful highly active antiretroviral therapy (HAART), are thought to play important roles in the immunopathogenesis of chronic HIV infection. Despite the important effects of the immunological and virological events of early HIV infection on subsequent disease progression, IL-12 production and immune activation in early infection remain under-defined. To quantify IL-12 production and immune activation during acute/early HIV infection, in the presence and absence of HAART, we performed a prospective, longitudinal study of participants in the Baltimore site of the Acute Infection and Early Disease Research Program, with cross-sectional comparison to healthy control subjects. PBMC cytokine productive capacity and plasma immune activation markers [soluble CD8 (sCD8), sCD4, granzyme B, neopterin, β2-microglobulin, sIL-2R, sTNFRI, sTNFRII, and IL-12p70] were quantified by ELISA. Notably, PBMC from patients with acute/early HIV infection exhibited in vivo IL-12p70 production along with increased, maximal in vitro IL-12 production. Further, despite evidence from plasma markers of generalized immune activation, no elevation in plasma levels of sCD4 was observed, suggesting relative blunting of in vivo CD4+ T cell activation from the beginning of HIV infection. Finally, despite successful virological responses to HAART, heightened in vivo CD8+ T cell activation, IL-12 production, and IFN activity were sustained for at least 6 months during primary HIV infection. These data underscore the need for comparative mechanistic analysis of the immunobiology of early and chronic HIV infection.

Study Objectives. To examine the frequency of highly active antiretroviral therapy (HAART) modifications, the reasons for these modifications, and toxicities of these drugs in patients receiving their first HAART regimen after a diagnosis of acute (< 2 mo from infection) or early (2–12 mo) human immunodeficiency virus (HIV) infection. Patients. Fifty-one patients who were enrolled in the Acute Infection and Early Disease Research Program at a Baltimore, Maryland, site between January 1, 1998, and April 30, 2002, and who chose to start HAART. Measurements and Main Results. Time from initiation of therapy to first modification—defined as change in any HAART drug without an interruption in therapy or as simultaneous discontinuation of all drugs within the regimen—and time from initiation of therapy to reinitiation of therapy were recorded, as well as reasons for modification and reinitiation. With a median follow-up of 1549 days, 21 (41%) of 51 patients received HAART continuously, but only 10 (20%) continued to receive their original regimen without any modification. Among the 41 patients (80%) who received modified therapy, the main reasons for the first modification were toxicity (16 patients), nonadherence (8), and new data on treatment efficacy or safety (8). Of 30 patients who stopped HAART, 18 restarted HAART at a later time. Conclusion. The high frequency of treatment modification among patients treated after acute or early HIV infection underscores the importance of determining the usefulness of antiretroviral therapy early in HIV infection, and the need for more tolerable regimens if HAART is to be started at this stage.

Objectives To evaluate the effectiveness of urine screening to detect HIV-infected individuals in high-prevalence communities. Methods Urine HIV testing was performed at 16 discrete events and four ongoing testing sites in Baltimore communities with a high incidence of HIV infection. When possible, positive urine test results were confirmed by blood testing. In addition, we attempted to obtain blood samples from subjects who reported a possible exposure to HIV but did not have a positive urine test. Results From February 1998 to August 2001, we screened 1718 persons. Overall, 210 persons (12%) were HIV-positive, of whom 169 (80%) had never previously tested positive; 87% of those who tested positive received their results, and most were referred for medical care. Conclusions Urine-based screening for HIV infection in high-prevalence inner city communities can be an effective tool for identifying and treating infected persons who are unaware of their infection.

T lymphocyte responses to human immunodeficiency virus (HIV) type 1 Gag were measured in 9 patients by interferon-gamma enzyme-linked immunospot assay at 3 time points within 12 months of infection. Patients with early recognition of HIV-1 Gag had lower subsequent HIV-1 load set points, as measured during the first 2 years of infection, compared with those of patients with undetectable Gag-specific responses (median, 4.27 vs. 5.05 log(10) HIV-1 RNA copies/mL, respectively; P=.028). An inverse correlation existed between the magnitude of the Gag-specific responses and the HIV-1 load set point (r=-0.733; P=.025). Early sustained T lymphocyte responses to HIV-1 Gag may be important for the establishment of virus load set point.

The mechanisms involved in the decline of CD4 and CD8 T-cells that lead to HIV-induced immune dysregulation are not clearly understood. We hypothesize that late-emerging strains of HIV, such as CXCR4-tropic (X4) virions, induce T-cell homeostasis failure by promoting significantly more bystander cell death, and immune exhaustion in naive CD4 and all CD8 T-cells, when compared to strain of HIV, such as CCR5-tropic (R5) virions, found early during the course of infection. In the reported study, inactivated X4 virions induced greater bystander cell death in sort-purified naive CD4 T-cells compared to R5 virions, which was significant ( p =0.013), and in memory CD8 T-cells, though the latter was not significant. A clearer understanding of the mechanisms involved in HIV-induced depletion of T-cell numbers and function could lead to therapies that prevent T-cell death and restore immune function. These therapies could improve current anti-retroviral and cure-related treatments by boosting the immune system's own ability to combat the virus.

The risk factors responsible for acute rheumatic fever (ARF) are complex, in part, because group A streptococcus (GAS) infection is a prerequisite for this disease. We attempted to differentiate socioeconomic from genetic risk factors by studying subjects in a Hawaii pediatric cardiology clinic who qualified for Medicaid. This ethnically diverse group was unique because they maintained a low socioeconomic but generally healthy lifestyle with more limited risks than those living in extremely impoverished conditions.Questionnaires were administered to consenting subjects in the clinic, who were divided into those diagnosed with ARF (n = 26) and those with other (primarily congenital) heart diseases (n = 41).The socioeconomic status of the ARF and non-ARF groups was lower than that of the Hawaii population in general, and little differences were noted between the groups. The ARF group, however, had slightly larger household sizes and more children than the non-ARF group. The greatest difference was in ethnicity. By the Fisher exact test, the number of Polynesians belonging to the ARF group was significantly greater than all other ethnicities (P = .005). Polynesians had an odds ratio4.80 of developing ARF, which increased to 6.33 when number of children per household was considered.The potential contribution of genetic predisposing factors for developing ARF was analyzed in subjects living in a homogeneously low socioeconomic level relative to the general Hawaii population. Polynesians were at highest risk when compared to other ethnicities living in similar socioeconomic conditions.