Scott Souza

Elevated Blood Pressure in HIV-Infected Individuals Receiving Highly Active Antiretroviral Therapy

Abstract Objective: We examined the effects of antiretroviral regimens on blood pressure (BP). Method: This retrospective study examined systolic and diastolic BP (SBP and DBP) measurements among participants of a State of Hawaii Department of Health program from January 1995 to July 2003. The change in BP during four consecutive 6-month visits was estimated using linear regression and was interpreted as the change in BP per year. BP changes among the antiretroviral treatment groups were compared to untreated controls. Results: Of 1,601 patients identified, 286 met the criteria for inclusion. After adjustment for baseline age, BP, and CD4+ count, there was an increase in SBP by 4.71 mmHg/year (p = .005) and DBP by 2.26 mmHg/year (p = .076) among patients initiating HAART. Among these patients, an increase of 4.75 mmHg/year in SBP (p = .002) and 1.96 mmHg/year in DBP (p = .042) was seen with HAART regimens containing a protease inhibitor (PI) but no nonnucleoside reverse transcriptase inhibitor (NNRTI). In NNRTI-containing HAART regimens without PIs, an increase of 3.21 mmHg/year in SBP (p = .011) and 2.62 mmHg/year in DBP (p = .050) was observed. No significant BP changes were noted with patients on regimens containing only nucleoside reverse transcriptase inhibitors (NRTIs). Conclusion: The use of NNRTI- or PI-containing HAART is associated with elevation of both SBP and DBP in HIV-infected individuals.

Fasting hyperinsulinemia and increased waist-to-hip ratios in non-wasting individuals with AIDS.

OBJECTIVE To identify metabolic and body composition changes associated with HIV-1 infection in a cross-sectional study of individuals stratified by immunologic status and body mass. DESIGN Metabolic abnormalities including glucose intolerance and changes in body morphology have recently been described in HIV-1-infected individuals following therapy with protease inhibitor-containing highly active anti-retroviral therapy. Although this is suggestive of a direct drug effect, the possibility that HIV infection may induce a tendency towards such underlying derangements should be considered. HIV-infected patients are heterogeneous with respect to immunologic status and body mass. In examining the underlying effect of HIV-1 on metabolic and body composition parameters, stratification by various immunologic and body mass categories may give divergent results that would not be detected otherwise. METHODS Thirty male participants were categorized into four cohorts: non-wasting HIV-seronegative controls, non-wasting HIV-infected patients with relatively intact immune function (CD4 cell count > 500 x 10(6)/l); non-wasting individuals with AIDS (CD4 cell count < 200 x 10(6)/l); and individuals with AIDS wasting. RESULTS Increased fasting plasma insulin and waist-to-hip ratios were found specifically in non-wasting individuals with AIDS compared with HIV-negative controls. CONCLUSIONS Our study emphasises the importance of both body mass and immune function in studying metabolic and body composition abnormalities associated with HIV-1 infection. The association of increased waist-to-hip ratios and hyperinsulinemia suggestive of insulin resistance in non-wasting individuals with AIDS suggest that the tendency towards these metabolic abnormalities may be related to the HIV infectious process or to factors associated with immunologic dysfunction.

Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter.

Objective: We evaluated regional brain volumes and cerebral metabolite levels as correlates of HIV DNA in peripheral blood mononuclear cells (PBMCs). Methods: In this cross-sectional study, 35 HIV+ subjects aged ≥40 years (25 with detectable PBMC HIV DNA; 10 with HIV DNA <10 copies/106 cells, the threshold of detection) and 12 seronegative controls underwent structural brain MRI and magnetic resonance spectroscopy at 3 T. HIV+ subjects were on combination antiretroviral therapy ≥1 year; all but 1 had plasma HIV RNA <50 copies/mL. We used logistic regression to evaluate relationships of likely predictor variables to the outcome of PBMC HIV DNA detectability in the HIV+ subjects. Effects of serostatus and HIV DNA on regional brain volumes (normalized to intracranial volume) and on metabolite ratios over creatine were evaluated by analyses of covariance, controlling for age. Results: Relative to the HIV+ group with undetectable HIV DNA, subjects with detectable HIV DNA demonstrated decreased volumes of cerebellar (−14%, p = 0.020) and total subcortical (−10%, p = 0.024) gray matter. Compared to healthy controls, only the detectable HIV DNA group showed significant (p < 0.05) enlargement of lateral ventricles and volumetric reductions of caudate, putamen, thalamus, hippocampus, nucleus accumbens, brainstem, total cortical gray matter, and cerebral white matter. Detectable HIV DNA was not associated with significantly altered cerebral metabolite levels. Conclusion: Inability to clear peripheral blood of HIV DNA is associated with regional brain atrophy in well-controlled HIV infection, supporting the involvement of peripheral viral reservoirs in the neuropathogenesis of persistent HIV-related neurocognitive disorders.

Short-term ezetimibe is well tolerated and effective in combination with statin therapy to treat elevated LDL cholesterol in HIV-infected patients.

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/μl, 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.

Acetyl-l-carnitine and nucleoside reverse transcriptase inhibitor-associated neuropathy in HIV infection.

Antiretroviral toxic neuropathy (ATN) is associated with dideoxynucleoside reverse transcriptase inhibitor use in patients infected with HIV, possibly as a result of mitochondrial toxicity. Acetyl‐l‐carnitine (ALC) has been linked to symptomatic improvement in ATN. We present an open‐label single‐arm pilot study to evaluate changes in intra‐epidermal nerve fibre (IENF) density and mitochondrial DNA (mtDNA) copies/cell among subjects treated with 3000 mg ALC daily.

Short-term effects of extended-release niacin on endothelial function in HIV-infected patients on stable antiretroviral therapy.

Objective:To assess the short-term effects of extended-release niacin (ERN) on endothelial function in HIV-infected patients with low high-density lipoprotein-cholesterol (HDL-c) levels. Methods:Randomized controlled study to determine the short-term effects of ERN on endothelial function, measured by flow-mediated vasodilation (FMD) of the brachial artery, in HIV-infected adults with low HDL-c. Participants on stable HAART with fasting HDL-c less than 40 mg/dl and low-density lipoprotein-cholesterol less than 130 mg/dl were randomized to ERN or control arms. ERN treatment started at 500 mg/night and titrated to 1500 mg/night for 12 weeks. Controls received the same follow-up but were not given ERN (no placebo). Participants were excluded if they had a history of cardiac disease, uncontrolled hypertension, diabetes mellitus, or were on lipid-lowering medications such as statins and fibrates. Change in FMD was compared between arms with respect to baseline HDL-c. Results:Nineteen participants were enrolled: 89% men, median age 50 years, 53% white/non-Hispanic, median CD4 cell count 493 cells/μl, and 95% of them had HIV RNA below 50 copies/ml. Participants receiving ERN had a median HDL-c (interquartile range) increase of 3.0 mg/dl (0.75 to 5.0) compared with −1.0 mg/dl in controls (−6.0 to 2.5), a P value is equal to 0.04. The median change in FMD was 0.91% (−2.95 to 2.21) for ERN and −0.48% (−2.65 to 0.98) for controls (P = 0.67). However, end of study FMD for ERN was significantly different from controls after adjusting for baseline differences in FMD and HDL-c, 6.36% (95% confidence interval 4.85–7.87) and 2.73% (95% confidence interval 0.95–4.51) respectively, a P value is equal to 0.048. Conclusion:This pilot study demonstrated that short-term niacin therapy could improve endothelial function in HIV-infected patients with low HDL-c.

Non-Classical Monocytes and Monocyte Chemoattractant Protein-1 (MCP-1) Correlate with Coronary Artery Calcium Progression in Chronically HIV-1 Infected Adults on Stable Antiretroviral Therapy

Background Persistent inflammation and immune activation has been hypothesized to contribute to increased prevalence of subclinical atherosclerosis and cardiovascular disease (CVD) risk in patients with chronic HIV infection. In this study, we examined the correlation of peripheral monocyte subsets and soluble biomarkers of inflammation to coronary artery calcium (CAC) progression, as measured by cardiac computed tomography scan. Methods We conducted a longitudinal analysis utilizing baseline data of 78 participants with HIV infection on stable antiretroviral therapy (ART) in the Hawaii Aging with HIV-Cardiovascular study who had available baseline monocyte subset analysis as well as CAC measurement at baseline and at 2-year follow up. Monocyte phenotypes were assessed from cryopreserved blood by flow cytometry and plasma was assayed for soluble biomarkers using antibody-coated beads in a high sensitivity Milliplex Luminex platform. Change in CAC over 2 years was analyzed as the primary outcome variable. Results Of all monocyte subsets and biomarkers tested, higher non-classical monocyte percentage (ρ = 0.259, p = 0.022), interleukin (IL)-6 (ρ = 0.311, p = 0.012), and monocyte chemoattractant protein (MCP)-1 (ρ = 0.524, p = <0.001) were significantly correlated to higher 2-year CAC progression in unadjusted Spearman’s correlation. Non-classical monocyte percentage (ρ = 0.247, p = 0.039), and MCP-1 (ρ = 0.487, p = <0.001), remained significantly correlated to 2-year CAC progression, while IL-6 was not (ρ = 0.209, p = 0.120) after adjustment for age, hypertension, diabetes mellitus, total/HDL cholesterol ratio, smoking history, and BMI. Conclusion The percentage of non-classical monocytes and plasma MCP-1 levels were independently associated with CAC progression and may be related to the progression of atherosclerosis and increased CVD risk associated with chronic HIV infection on stable ART.

HIV-Associated Wasting in the Era of Highly Active Antiretroviral Therapy: A Syndrome of Residual HIV Infection in Monocytes and Macrophages?

Human immunodeficiency virus (HIV) infection in peripheral blood mononuclear cells (PBMCs) might be influencing the development of wasting in the era of potent antiretroviral therapy. In a retrospective study of 57 subjects, HIV proviral DNA levels in PBMCs were higher in subjects whose body weight decreased by >5% one year after initiation of highly active antiretroviral therapy, compared with subjects whose body weight was stable or increased (median HIV proviral DNA load, 8.9 vs. 0.9 copies/10(6) PBMCs; P = .006).

Effect of extended-release niacin on hormone-sensitive lipase and lipoprotein lipase in patients with HIV-associated lipodystrophy syndrome.

Background: HIV-associated lipodystrophy syndrome is strongly associated with antiretroviral treatment in patients with human immunodeficiency virus (HIV). Niacin is thought to affect hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) expression in peripheral and intra-abdominal fat (IAF). Objective: This study investigated the effect of extended-release niacin (ERN) on adipose HSL and LPL expression in patients with HIV-associated lipodystrophy syndrome. Methods: Changes in IAF and peripheral fat content and HSL and LPL expression were examined in 4 HIV-infected patients recruited from a prospective study treated with ERN. Patients underwent limited 8 slice computerized tomography abdominal scans, dual-energy X-ray absorptiometry scans, and skin punch biopsies of the mid-thigh at baseline and after 12 weeks of ERN. All subjects were on stable highly active antiretroviral therapy prior to and during the study. Changes in body habitus were self-reported. Results: Normalized HSL expression decreased in 3 patients and normalized LPL expression increased in all 4 patients when comparing pre- and post-ERN treated samples. All subjects showed a decrease in total cholesterol (TC) and triglyceride (TG) levels. Conclusions: Preliminary analysis suggests ERN may induce changes in HSL and LPL expression. This method is a feasible approach to identify changes in adipose RNA expression involved with lipolysis.

Non-classical monocytes predict progression of carotid artery bifurcation intima-media thickness in HIV-infected individuals on stable antiretroviral therapy

Background: Inflammation may contribute to cardiovascular disease (CVD) among antiretrovirally suppressed HIV-infected individuals. We assessed relationships of monocyte, CD8 T-cell activation and plasma biomarkers to changes in carotid artery intima-media thickness (CIMT). Methods: Longitudinal study of HIV-infected subjects ≥40 years and on stable antiretroviral therapy (ART) ≥3 months. Peripheral blood mononuclear cells were immunophenotyped by multiparameteric flow cytometry to quantify classical (CD14++CD16–), intermediate (CD14++CD16+), non-classical (CD14low/+CD16++) and transitional (CD14+CD16–) monocyte subsets and activated (CD38+HLA-DR+) CD8+ T-cells at baseline. Plasma biomarkers were assessed by multiplex Luminex assay. High-resolution B-mode ultrasounds of right carotid arteries were obtained. Changes in CIMT over two years at the right common carotid artery (CIMTCCA) and right bifurcation (CIMTBIF) were outcome variables. Results: We studied 50 subjects: 84% male, median age 49 (Q1, Q3; 46, 56) years, median CD4 count 461 (317, 578) cells/mm3, and with HIV RNA ≤ 50 copies/mL in 84%. Change in CIMTBIF correlated with log values of baseline absolute count of non-classical monocytes (r = 0.37, p = 0.020), and with MCP-1 (r = 0.42, p = 0.0024) and TNF-α (r = 0.30, p = 0.036) levels. In multivariable linear regression, only non-classical monocytes and MCP-1 predicted the change in CIMTBIF, independent of Framingham Risk Score and baseline CIMTBIF. No correlation was noted between CD8 T-cell activation and CIMTBIF change. Monocyte subsets, CD8 T-cell activation, and biomarker concentrations were not correlated with changes in CIMTCCA. Conclusions: Our findings highlight the role of non-classical monocytes and MCP-1 in the progression of CIMTBIF in HIV-infected individuals on stable ART independent of traditional cardio-metabolic risk factors.