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Objective: To assess the effect of HIV infection and combined antiretroviral therapy (c-ART) on various proatherogenic biomarkers and lipids and to investigate their relationship with subclinical atherosclerosis in a cohort of treatment-naive HIV-infected patients., Methods: We performed a prospective, comparative, multicenter study of 2 groups of treatment-naive HIV-infected patients (group A, CD4>500 cells/μL, not starting c-ART; and group B, CD4<500 cells/μL, starting c-ART at baseline) and a healthy control group. Laboratory analyses and carotid ultrasound were performed at baseline and at months 12 and 24. The parameters measured were low-density lipoprotein (LDL) particle phenotype, lipoprotein-associated phospholipase A2 (Lp-PLA2), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), sCD14, sCD163, monocyte chemoattractant protein-1(MCP-1), and asymmetric dimethylarginine (ADMA). A linear mixed model based on patient clusters was used to assess differences in biomarkers between the study groups and over time., Results: The study population comprised 62 HIV-infected patients (group A, n = 31; group B, n = 31) and 22 controls. Age was 37 (30-43) years, and 81% were men. At baseline, the HIV-infected patients had a worse LDL particle phenotype and higher plasma concentration of sCD14, sCD163, hs-CRP, and LDL-Lp-PLA2 than the controls. At month 12, there was an increase in total cholesterol (p = 0.002), HDL-c (p = 0.003), and Apo A-I (p = 0.049) and a decrease in sCD14 (p = <0.001) and sCD163 (p<0.001), although only in group B. LDL particle size increased in group B at month 24 (p = 0.038). No changes were observed in group A or in the healthy controls. Common carotid intima-media thickness increased in HIV-infected patients at month 24 (Group A p = 0.053; group B p = 0.048). Plasma levels of sCD14, sCD163, and hs-CRP correlated with lipid values., Conclusions: In treatment-naive HIV-infected patients, initiation of c-ART was associated with an improvement in LDL particle phenotype and inflammatory/immune biomarkers, reaching values similar to those of the controls. HIV infection was associated with progression of carotid intima-media thickness., Competing Interests: The authors have declared that no competing interst exist.

Aim: We comprehensively analyzed how hepatitis C virus (HCV) eradication by interferon (IFN)-free direct-acting-antiviral-agents (DAAs) affects liver steatosis and atherogenic risk., Methods: Patients treated with IFN-free-DAAs who underwent transient elastography before and at 24-weeks post-treatment, including controlled attenuation parameter (CAP), and achieved sustained viral response (SVR) were enrolled. The association between changes in liver steatosis, lipid-metabolism, and genetic and clinical factors was analyzed., Results: A total of 117 patients were included. The mean CAP and low-density lipoprotein cholesterol (LDL-C) levels were significantly elevated at SVR24. However, baseline LDL-C and CAP values were significantly negatively correlated with changes in these values after HCV eradication, indicating that in patients with high baseline values, the values generally decreased after HCV eradication. Mean small-dense LDL-C (sdLDL-C), which has greater atherogenic potential, was significantly elevated only in patients with both dyslipidemia (LDL-C >140 mg/dL) and liver steatosis (CAP >248 dB/m) at SVR24. Those patients had significant higher baseline BMI, LDL-C, and total-cholesterol levels., Conclusions: Generally, successful HCV eradication by IFN-free-DAAs decreases CAP and LDL-C in patients with high baseline values. However, elevated LDL-C was accompanied with elevated sdLDL-C only in patients with liver steatosis and dyslipidemia at SVR24; therefore, those patients may require closer monitoring., Competing Interests: Professor Naoya Sakamoto received lecture fees from Bristol Myers Squibb and Pharmaceutical K.K, grants and endowments from MSD K. K and Chugai Pharmaceutical Co., Ltd, and a research grant from Gilead Sciences Inc. Dr. Goki Suda received research grants from Bristol Myers Squibb. The other authors have nothing to disclose. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Objectives: HIV-infected patients are at increased risk for cardiovascular disease (CVD). However, general population CVD risk prediction equations that identify HIV-infected patients at elevated risk have not been widely assessed in sub-Saharan African (SSA)., Methods: HIV-infected adults from 30-50 years of age with documented viral suppression were enrolled into a cross-sectional study in Gaborone, Botswana. Participants were screened for CVD risk factors. Bilateral carotid intima-media thickness (cIMT) was measured and 10-year predicted risk of cardiovascular disease was calculated using the Pooled Cohorts Equation for atherosclerotic CVD (ASCVD) and the 2008 Framingham Risk Score (FRS) (National Cholesterol Education Program III-NCEP III). ASCVD ≥7.5%, FRS ≥10%, and cIMT≥75th percentile were considered elevated risk for CVD. Agreement in classification of participants as high-risk for CVD by cIMT and FRS or ASCVD risk score was assessed using McNemar`s Test. The optimal cIMT cut off-point that matched ASCVD predicted risk of ≥7.5% was assessed using Youden's J index., Results: Among 208 HIV-infected patients (female: 55%, mean age 38 years), 78 (38%) met criteria for ASCVD calculation versus 130 (62%) who did not meet the criteria. ASCVD classified more participants as having elevated CVD risk than FRS (14.1% versus 2.6%, McNemar's exact test p = 0.01), while also classifying similar proportion of participants as having elevated CVD like cIMT (14.1% versus 19.2%, McNemar's exact test p = 0.34). Youden's J calculated the optimal cut point at the 81st percentile for cIMT to correspond to an ASCVD score ≥7.5% (sensitivity = 72.7% and specificity = 88.1% with area under the curve for the receiver operating characteristic [AUC] of 0.82, 95% Mann-Whitney CI: 0.66-0.99)., Conclusion: While the ASCVD risk score classified more patients at elevated CVD risk than FRS, ASCVD score classified similar proportion of patients as high risk when compared with established subclinical atherosclerosis. However, potential CVD risk category misclassification by established equations such as ASCVD may still exist among HIV-infected patients; hence there is still a need for development of a CVD risk prediction equation tailored to HIV-infected patients in SSA.

Background: HIV patients on antiretroviral therapy have shown elevated incidence of dyslipidemia, lipodystrophy, and cardiovascular disease (CVD). Most studies, however, focus on cohorts from developed countries, with less data available for these co-morbidities in Ethiopia and sub-Saharan Africa., Methods: Adult HIV-negative (n = 36), treatment naïve (n = 51), efavirenz (EFV)-treated (n = 91), nevirapine (NVP)-treated (n = 95), or ritonavir-boosted lopinavir (LPV/r)-treated (n=44) subjects were recruited from Black Lion Hospital in Addis Ababa, Ethiopia. Aortic pressure, augmentation pressure, and pulse wave velocity (PWV) were measured via applanation tonometry and carotid intima-media thickness (cIMT) and carotid arterial stiffness, and brachial artery flow-mediated dilation (FMD) were measured via non-invasive ultrasound. Body mass index, waist-to-hip circumference ratio (WHR), skinfold thickness, and self-reported fat redistribution were used to quantify lipodystrophy. CD4+ cell count, plasma HIV RNA levels, fasting glucose, total-, HDL-, and LDL-cholesterol, triglycerides, hsCRP, sVCAM-1, sICAM-1, leptin and complete blood count were measured., Results: PWV and normalized cIMT were elevate and FMD impaired in EFV- and LPV/r-treated subjects compared to NVP-treated subjects; normalized cIMT was also elevated and FMD impaired in the EFV- and LPV/r-treated subjects compared to treatment-naïve subjects. cIMT was not statistically different across groups. Treated subjects exhibited elevated markers of dyslipidemia, inflammation, and lipodystrophy. PWV was associated with age, current EFV and LPV/r used, heart rate, blood pressure, triglycerides, LDL, and hsCRP, FMD with age, HIV duration, WHR, and glucose, and cIMT with age, current EFV use, skinfold thickness, and blood pressure., Conclusions: Current EFV- or LPV/r-treatment, but not NVP-treatment, correlated with elevated markers of atherosclerosis, which may involve mechanisms distinct from traditional risk factors.

Background and Aims: Increasing evidence demonstrates that hepatitis C virus (HCV) infection is associated with atherosclerosis. However, there are contrasting findings in several studies that the atherosclerotic burden is not associated with HCV infections. Therefore, we performed a meta-analysis to clarify if HCV infection is associated with atherosclerosis compared to non-infected people., Methods: Standard guidelines for performance of meta-analysis were followed., Results: A thorough database search performed by two independent investigators identified 14 eligible studies for analysis. The data from 11 studies were synthesized to report unadjusted odds ratios (ORs) for carotid atherosclerosis; the pooled unadjusted OR (95% confidence interval (CI)) was 1.65 (1.21, 2.09). By synthesizing the data from 8 studies to report adjusted ORs for carotid atherosclerosis the pooled multi-confounder adjusted OR (95% CI) was 1.76 (1.20, 2.32). However, the numbers of studies on coronary or femoral atherosclerosis were limited and not enough for analysis., Conclusions: Our meta-analysis indicates that HCV infection is associated with carotid atherosclerosis independent of classical risk factors. Therefore, we would recommend for HCV infected patients to be counseled on their risk for carotid atherosclerosis.

Objective: We investigated the relationship of the Herpesviridiae with inflammation and subclinical atherosclerosis in HIV-infected patients., Methods: Prospective study including virologically suppressed HIV-infected patients. IgG antibodies against herpesviruses, carotid intima-media thickness (cIMT), endothelial function through flow-mediated dilatation (FMD) of the brachial artery, and blood atherosclerosis biomarkers (hsCRP, TNF-α, IL-6, MCP-1, MDA, sCD14, sCD163, VCAM-1, ICAM-1, D-dimer, and PAI-1) were measured., Results: 136 patients with HIV viral load <200 copies/ml were included. 93.4% patients were infected with herpes simplex virus type-1, 55.9% with herpes simplex virus type-2, 97.1% with varicella-zoster virus, 65.4% with human herpesvirus-6, 91.2% with cytomegalovirus, and 99.3% with Epstein-Barr virus. Previous AIDS diagnosis was associated with higher cytomegalovirus IgG titers (23,000 vs 17,000 AU, P = 0.011) and higher varicella-zoster virus IgG titers (3.19 vs 2.88 AU, P = 0.047), and there was a positive correlation of the Framingham risk score with IgG levels against cytomegalovirus (Spearman's Rho 0.216, P = 0.016) and Herpes simplex virus-2 (Spearman's Rho 0.293, P = 0.001). IgG antibodies against cytomegalovirus correlated in adjusted analysis with the cIMT (P = 0.030). High seropositivity for varicella-zoster virus (OR 2.91, 95% CI 1.05-8.01, P = 0.039), and for cytomegalovirus (OR 3.79, 95% CI 1.20-11.97, P = 0.023) were predictors for the highest quartile of the cIMT in adjusted analyses. PAI-1 levels were independently associated with cytomegalovirus IgG titers (P = 0.041), IL-6 and ICAM-1 levels with varicella-zoster virus IgG (P = 0.046 and P = 0.035 respectively), and hsCRP levels with Herpes simplex virus-2 IgG (P = 0.035)., Conclusion: In virologically suppressed HIV-infected patients, antibody responses against herpesviruses are associated with subclinical atherosclerosis, and with increased inflammation and coagulation biomarkers.

Cytomegalovirus (CMV) infection is a common infection in adults (seropositive 60-99% globally), and is associated with cardiovascular diseases, in line with risk factors such as hypertension and atherosclerosis. Several viral infections are linked to hypertension, including human herpes virus 8 (HHV-8) and HIV-1. The mechanisms of how viral infection contributes to hypertension or increased blood pressure are not defined. In this report, the role of CMV infection as a cause of increased blood pressure and in forming aortic atherosclerotic plaques is examined. Using in vivo mouse model and in vitro molecular biology analyses, we find that CMV infection alone caused a significant increase in arterial blood pressure (ABp) (p<0.01 approximately 0.05), measured by microtip catheter technique. This increase in blood pressure by mouse CMV (MCMV) was independent of atherosclerotic plaque formation in the aorta, defined by histological analyses. MCMV DNA was detected in blood vessel samples of viral infected mice but not in the control mice by nested PCR assay. MCMV significantly increased expression of pro-inflammatory cytokines IL-6, TNF-alpha, and MCP-1 in mouse serum by enzyme-linked immunosorbent assay (ELISA). Using quantitative real time reverse transcriptase PCR (Q-RT-PCR) and Western blot, we find that CMV stimulated expression of renin in mouse and human cells in an infectious dose-dependent manner. Co-staining and immunofluorescent microscopy analyses showed that MCMV infection stimulated renin expression at a single cell level. Further examination of angiotensin-II (Ang II) in mouse serum and arterial tissues with ELISA showed an increased expression of Ang II by MCMV infection. Consistent with the findings of the mouse trial, human CMV (HCMV) infection of blood vessel endothelial cells (EC) induced renin expression in a non-lytic infection manner. Viral replication kinetics and plaque formation assay showed that an active, CMV persistent infection in EC and expression of viral genes might underpin the molecular mechanism. These results show that CMV infection is a risk factor for increased arterial blood pressure, and is a co-factor in aortic atherosclerosis. Viral persistent infection of EC may underlie the mechanism. Control of CMV infection can be developed to restrict hypertension and atherosclerosis in the cardiovascular system.