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1.  Carotid Intima-Media Thickness and Plasma Asymmetric Dimethylarginine in Mexican Children Exposed to Inorganic Arsenic 
Environmental Health Perspectives  2013;121(9):1090-1096.
Background: Arsenic exposure is a risk factor for atherosclerosis in adults, but there is little information on arsenic and early risk biomarkers for atherosclerosis in children. Carotid intima-media thickness (cIMT) is an indicator of subclinical atherosclerotic burden that has been associated with plasma asymmetric dimethylarginine (ADMA), a predictor of cardiovascular disease risk.
Objectives: The aim of this study was to investigate associations of arsenic exposure with cIMT, ADMA, and endothelial adhesion molecules [soluble intercellular cell adhesion molecule-1 (sICAM-1); soluble vascular cell adhesion molecule-1 (sVCAM-1)] in children who had been exposed to environmental inorganic arsenic (iAs).
Methods: We conducted a cross-sectional study in 199 children 3–14 years of age who were residents of Zimapan, México. We evaluated cIMT using ultrasonography, and plasma lipid profiles by standard methods. We analyzed ADMA, sICAM-1, and sVCAM-1 by ELISA, and measured the concentrations of total speciated arsenic (tAs) in urine using hydride generation cryotrapping atomic absorption spectrometry.
Results: In the multiple linear regression model for cIMT, tAs categories were positively associated with cIMT increase. The estimated cIMT diameter was greater in 35- to 70-ng/mL and > 70-ng/mL groups (0.035 mm and 0.058 mm per 1-ng/mL increase in urinary tAs, respectively), compared with the < 35-ng/mL group. In addition to tAs level, plasma ADMA was a significant predictor of cIMT. In the adjusted regression model, cIMT, percent iAs, and plasma sVCAM-1 were significant predictors of ADMA levels (e.g., 0.419-μmol/L increase in ADMA per 1-mm increase in cIMT).
Conclusions: Arsenic exposure and plasma ADMA levels were positively associated with cIMT in a population of Mexican children with environmental arsenic exposure through drinking water.
Citation: Osorio-Yáñez C, Ayllon-Vergara JC, Aguilar-Madrid G, Arreola-Mendoza L, Hernández-Castellanos E, Barrera-Hernández A, De Vizcaya-Ruíz A, Del Razo LM. 2013. Carotid intima-media thickness and plasma asymmetric dimethylarginine in Mexican children exposed to inorganic arsenic. Environ Health Perspect 121:1090–1096; http://dx.doi.org/10.1289/ehp.1205994
doi:10.1289/ehp.1205994
PMCID: PMC3764073  PMID: 23757599
2.  Increased Carotid Intima-Media Thickness Associated with Antibody Responses to Varicella-Zoster Virus and Cytomegalovirus in HIV-Infected Patients 
PLoS ONE  2013;8(5):e64327.
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.
doi:10.1371/journal.pone.0064327
PMCID: PMC3662719  PMID: 23717597
3.  Atherosclerosis in early rheumatoid arthritis: very early endothelial activation and rapid progression of intima media thickness 
Arthritis Research & Therapy  2010;12(4):R158.
Introduction
In this study we aimed to investigate whether there are indications of premature atherosclerosis, as measured by endothelial dependent flow-mediated dilation (ED-FMD) and intima media thickness (IMT), in patients with very early RA, and to analyze its relation to biomarkers of endothelial dysfunction, taking inflammation and traditional cardiovascular disease (CVD) risk factors into account.
Methods
Patients from the three northern counties of Sweden diagnosed with early RA are followed in an ongoing prospective study of CVD co-morbidity. Of these, all patients aged ≤60 years were consecutively included in this survey of CVD risk factors (n = 79). Forty-four age and sex matched controls were included. IMT of common carotid artery and ED-FMD of brachial artery were measured using ultrasonography. Blood was drawn for analysis of lipids, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA)-mass, VonWillebrand factor (VWF), soluble intercellular adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), sE-selectin, sL-selectin and monocyte chemotactic protein-1 (MCP-1). In a subgroup of 27 RA patients and their controls the ultrasound measurements were reanalysed after 18 months.
Results
There were no significant differences between RA patients and controls in terms of IMT or ED-FMD at the first evaluation. However after 18 months there was a significant increase in the IMT among the patients with RA (P < 0.05). Patients with RA had higher levels of VWF, sICAM-1 (P < 0.05) and of MCP-1 (P = 0.001) compared with controls. In RA, IMT was related to some of the traditional CVD risk factors, tPA-mass, VWF (P < 0.01) and MCP-1 and inversely to sL-selectin (P < 0.05). In RA, ED-FMD related to sL-selectin (P < 0.01). DAS28 at baseline was related to PAI-1, tPA-mass and inversely to sVCAM-1 (P < 0.05) and sL-selectin (P = 0.001).
Conclusions
We found no signs of atherosclerosis in patients with newly diagnosed RA compared with controls. However, in patients with early RA, IMT and ED-FMD were, to a greater extent than in controls, related to biomarkers known to be associated with endothelial dysfunction and atherosclerosis. After 18 months, IMT had increased significantly in RA patients but not in controls.
doi:10.1186/ar3116
PMCID: PMC2945061  PMID: 20712865
4.  Risk of Hip Fracture Associated with Hepatitis C Virus Infection and Hepatitis C/HIV Coinfection 
Hepatology (Baltimore, Md.)  2012;56(5):1688-1698.
Hepatitis C virus (HCV) infection has been associated with reduced bone mineral density, but its association with fracture rates is unknown, particularly in the setting of human immunodeficiency virus (HIV) coinfection. Our objectives were to determine whether persons with HCV infection alone are at increased risk for hip fracture compared to uninfected individuals and to examine if the risk of hip fracture is higher among HCV/HIV-coinfected persons compared to those with HCV alone, those with HIV alone, and those uninfected with either virus. We conducted a cohort study in 36,950 HCV/HIV-coinfected, 276,901HCV-monoinfected, 95,827 HIV-monoinfected, and 3,110,904 HCV/HIV-uninfected persons within the U.S. Medicaid populations of California, Florida, New York, Ohio, and Pennsylvania (1999–2005). Incidence rates of hip fracture were lowest among uninfected persons (1.29 events/1000 person-years), increased with the presence of either HIV infection (1.95 events/1000 person-years) or HCV infection (2.69 events/1000 person-years), and were highest among HCV/HIV-coinfected individuals (3.06 events/1000 person-years). HCV/HIV coinfection was associated with an increased relative hazard (adjusted hazard ratio [95% confidence interval]) of hip fracture compared to HCV-monoinfected (1.38 [1.25–1.53]), HIV-monoinfected (females: 1.76 [1.44–2.16]; males: 1.36 [1.20–1.55]), and uninfected persons (females: 2.65 [2.21–3.17]; males: 2.20 [1.97–2.47]). HCV monoinfection was associated with an increased risk of hip fracture compared to uninfected individuals, and the relative increase was highest in the youngest age groups (females, 18–39 years: 3.56 [2.93–4.32]; males, 18–39 years: 2.40 [2.02–2.84]).
Conclusion
Among Medicaid enrollees, HCV/HIV coinfection was associated with increased rates of hip fracture compared to HCV-monoinfected, HIV-monoinfected, and HCV/HIV-uninfected persons. HCV-monoinfected patients had an increased risk of hip fracture compared to uninfected individuals.
doi:10.1002/hep.25866
PMCID: PMC3433632  PMID: 22619086
Hepatitis C virus; HCV; HIV; fracture; coinfection
5.  Chronic Kidney Disease (CKD) after Liver Transplantation in HIV/ HCV Coinfected versus HIV/non-HCV Infected Recipients: Results from the NIH Multi-Site Study 
Hepatitis C virus (HCV) and Human Immunodeficiency Virus (HIV) are both associated with chronic kidney disease (CKD), a major complication after orthotopic liver transplantation (OLT). The aim of this study was to assess predictors of post-OLT CKD in HIV/HCV coinfected versus HIV/non-HCV infected recipients.
METHODS
Data from the NIH Solid Organ Transplantation in HIV: Multi-Site Study of 116 OLT recipients (35 HIV/non-HCV and 81 HIV/HCV co-infected) from 2003 to 2010 were analyzed for pre-transplant CKD prevalence (estimated glomerular filtration rate (eGFR) < 60 ml/min for ≥ 3 months) and incidence of CKD up to 3 years post-transplant. Proportional hazards models were performed to assess predictors of post-transplant CKD. A contemporaneous cohort of HCV monoinfected transplant recipients from the SRTR database was also analyzed.
RESULTS
Median age at transplant was 48 years, serum creatinine was 1.1 mg/dl, and median eGFR was 77 ml/min. Thirty-four patients had suspected pre-transplant CKD; 20 of these (59%) had post-transplant CKD. Among the 82 patients without pre-transplant CKD (26 HIV/non-HCV and 56 HIV/HCV coinfected), the cumulative incidence of stage 3 CKD at 3 years post-OLT was 62% (55% HIV/non-HCV versus 65% HIV/HCV coinfected) and stage 4/5 CKD was 8% (0% HIV/non-HCV versus 12% HIV/HCV coinfected). In multivariate proportional hazards analysis, older age (HR 1.05 per year; p 0.03) and CD4 count (HR 0.90 per 50 cells/µL; p 0.01) were significant predictors of CKD. HCV coinfection was significantly associated with stage 4/5 CKD (HR 10.8; p 0.03) after adjustment for age on multivariate analysis. The cumulative incidence of stage 4/5 CKD was significantly higher in HIV/HCV coinfected patients compared to HIV/non-HCV and HCV monoinfected transplant recipients (p=0.001).
CONCLUSIONS
CKD occurs frequently in HIV infected transplant recipients. Predictors of post-transplant CKD include older age, and lower post-transplant CD4 count. HCV co-infection is associated with a higher incidence of stage 4/5 CKD.
doi:10.1002/lt.23648
PMCID: PMC3667971  PMID: 23512786
6.  National trends in hospitalization and mortality rates for patients with HIV, HCV, or HIV/HCV coinfection from 1996–2010 in the United States: a cross-sectional study 
BMC Infectious Diseases  2014;14(1):536.
Background
The comparative impact of chronic viral monoinfection versus coinfection on inpatient outcomes and health care utilization is relatively unknown. This study examined trends, inpatient utilization, and hospital outcomes for patients with HIV, HCV, or HIV/HCV coinfection.
Methods
Data were from the 1996–2010 National Hospital Discharge Surveys. Hospitalizations with primary ICD-9-CM codes for HIV or HCV were included for HIV and HCV monoinfection, respectfully. Coinfection included both HIV and HCV codes. Demographic characteristics, select comorbidities, procedural interventions, average hospital length of stay (LOS), and discharge status were compared by infection status (HIV, HCV, HIV/HCV). Annual disease estimates and survey weights were used to generate hospitalization rates.
Results
~6.6 million hospitalizations occurred in patients with HIV (39%), HCV (56%), or HIV/HCV (5%). The hospitalization rate (hospitalizations per 100 persons with infection) decreased in the HIV group (29.8 in 1996; 5.3 in 2010), decreased in the HIV/HCV group (2.0 in 1996; 1.5 in 2010), yet increased in the HCV group (0.2 in 1996; 0.9 in 2010). Median LOS from 1996 to 2010 (days, interquartile range) decreased in all groups: HIV, 6 (3–10) to 4 (3–8); HCV, 5 (3–9) to 4 (2–6); HIV/HCV, 6 (4–11) to 4 (2–7). Age-adjusted mortality rates decreased for all three groups. The rate of decline was least pronounced for those with HCV monoinfection.
Conclusion
Hospitalizations have declined more rapidly for patients with HIV infection (including HIV/HCV coinfection) than for patients with HCV infection. This growing disparity between HIV and HCV underscores the need to allocate more resources to HCV care in hopes that similar large-scale improvements can also be accomplished for patients with HCV.
doi:10.1186/1471-2334-14-536
PMCID: PMC4287456  PMID: 25300638
HIV; HCV; Coinfection; Hospitalization; Health care utilization
7.  HIV/HCV coinfection ameliorates the atherogenic lipoprotein abnormalities of HIV infection 
AIDS (London, England)  2014;28(1):49-58.
Background
Higher levels of small low-density lipoprotein (LDL) and lower levels of high-density lipoprotein (HDL) subclasses have been associated with increased risk of cardiovascular disease. The extent to which HIV infection and HIV/HCV coinfection are associated with abnormalities of lipoprotein subclasses is unknown.
Methods
Lipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy in plasma samples from 569 HIV-infected and 5948 control participants in the FRAM, CARDIA and MESA studies. Multivariable regression was used to estimate the association of HIV and HIV/HCV coinfection with lipoprotein measures with adjustment for demographics, lifestyle factors, and waist-to-hip ratio.
Results
Relative to controls, small LDL levels were higher in HIV-monoinfected persons (+381 nmol/L, p<.0001), with no increase seen in HIV/HCV coinfection (−16.6 nmol/L). Levels of large LDL levels were lower (−196 nmol/L, p<.0001) and small HDL were higher (+8.2 μmol/L, p<.0001) in HIV-monoinfection with intermediate values seen in HIV/HCV-coinfection. Large HDL levels were higher in HIV/HCV-coinfected persons relative to controls (+1.70 μmol/L, p<.0001), whereas little difference was seen in HIV-monoinfected persons (+0.33, p=0.075). Within HIV-infected participants, HCV was associated independently with lower levels of small LDL (−329 nmol/L, p<.0001) and small HDL (−4.6 μmol/L, p<.0001), even after adjusting for demographic and traditional cardiovascular risk factors.
Conclusion
HIV-monoinfected participants had worse levels of atherogenic LDL lipoprotein subclasses compared with controls. HIV/HCV coinfection attenuates these changes, perhaps by altering hepatic factors affecting lipoprotein production and/or metabolism. The effect of HIV/HCV coinfection on atherosclerosis and the clinical consequences of low small subclasses remain to be determined.
doi:10.1097/QAD.0000000000000026
PMCID: PMC4267724  PMID: 24136113
HIV infection; HCV infection; lipoproteins; cardiovascular disease
8.  Quantification of hepatic FOXP3+ T‐lymphocytes in HIV/hepatitis C coinfection 
Journal of Viral Hepatitis  2013;21(4):251-259.
Summary
Coinfection with HIV adversely impacts every stage of hepatitis C (HCV) infection. Liver damage in HCV infection results from host antiviral responses rather than direct viral pathogenesis. Despite depressed cellular immunity, coinfected patients show accelerated hepatic fibrosis compared with HCV monoinfected patients. This paradox is poorly understood. T‐regulatory (Treg) cells (CD4+ and FOXP3+) are hypothesized to limit hepatic damage in HCV. Our hypothesis was that reduced frequency of hepatic Treg in HIV/HCV coinfection compared with HCV monoinfection may explain poorer outcomes. We quantified FOXP3+, CD4+, CD8+ and CD20+ cells in liver biopsies of 35 male subjects matched by age and ISHAK fibrosis score, 12 HIV monoinfected, 11 HCV monoinfected and 12 HIV/HCV coinfected. Cell counts were performed using indirect immunohistochemical staining and light microscopy. HIV/HCV coinfected subjects had fewer hepatic FOXP3+ (P = 0.031) and CD4+ cells (P = 0.001) than HCV monoinfected subjects. Coinfected subjects had more hepatic CD8+ cells compared with HCV monoinfected (P = 0.023), and a lower ratio of FOXP3+ to CD8+ cells (0.08 vs 0.27, P < 0.001). Multivariate analysis showed number of CD4+ cells controlled for differences in number of FOXP3+ cells. Fewer hepatic FOXP3+ and CD4+ cells in HIV/HCV coinfection compared with HCV monoinfection suggests lower Treg activity, driven by an overall loss of CD4+ cells. Higher number of CD8+ cells in HIV/HCV coinfection suggests higher cytotoxic activity. This may explain poorer outcomes in HIV/HCV coinfected patients and suggests a potential mechanism by which highly active antiretroviral therapy may benefit these patients.
doi:10.1111/jvh.12141
PMCID: PMC4159582  PMID: 24597693
coinfection; FOXP3 protein; hepacivirus; HIV; human; liver; regulatory; T‐lymphocytes
9.  Clinicopathologic correlates of hepatitis C virus in brain: A pilot study 
Journal of neurovirology  2008;14(1):17-27.
Hepatitis C virus (HCV) has been detected in the brain tissues of 10 individuals reported to date; it is unclear what clinical factors are associated with this, and with what frequency it occurs. Accordingly, a pilot analysis utilizing reverse transcriptase–polymerase chain reaction (RT- PCR) to detect and sequence HCV in premortem plasma and postmortem brain and liver from 20 human immunodeficiency virus (HIV)-infected and 10 HIV-naïve individuals was undertaken. RNA encoding the first 126 amino acids of the HCV E1 envelope protein and the majority of the E1 signal sequence was analyzed in parallel with an 80-base-long segment of the 5′ untranslated region (UTR). Liver HCV was detected only in subjects with premortem HCV viremia (10 HIV-infected and 3 HIV-naïve). Brain HCV was detected in 6/10 HCV/HIV-coinfected and 1/3 HCV-monoinfected subjects. In the setting of HIV, the magnitude of plasma HCV load did not correlate with the presence of brain HCV. However, coinfected patients with brain HCV were more often off antiretroviral therapy and tended to have higher plasma HIV loads than those with HCV restricted to liver. Furthermore, premortem cerebrospinal fluid (CSF) analysis revealed that HCV/HIV-coinfected patients with brain HCV had detectable CSF HIV, whereas those without brain HCV had undetectable CSF HIV loads (P = .0205). Neuropsychologic tests showed a trend for hierarchical impairment of abstraction/executive functioning in HIV/HCV coinfection, with mean T scores for HIV monoinfected patients 43.2 (7.3), for liver-only HCV 39.5 (9.0), and for those with HCV in brain and liver 33.2 (5.1) (P = .0927). Predominant brain HCV sequences did not match those of the plasma or liver in 4 of the 6 coinfected patients analyzed. We conclude that in the setting of HIV/HCV coinfection, brain HCV is a common phenomenon unrelated to the magnitude of HCV viremia, but related to active HIV disease and detectable CSF HIV. Furthermore, there is sequence evidence of brain compartmentalization. Differences in abstraction/executive function of HCV/HIV coinfected patients compared to HIV monoinfected warrant further studies to determine if neuropsychiatric effects are predicated upon brain infection.
doi:10.1080/13550280701708427
PMCID: PMC2729451  PMID: 18300072
brain; cognition; hepatitis C virus; HIV
10.  Carotid intima media thickness is associated with body fat abnormalities in HIV-infected patients 
BMC Infectious Diseases  2014;14:348.
Background
HIV-infected patients may be at increased risk of cardiovascular (CV) events, and lipodystrophy is generally associated with proatherogenic metabolic disturbances. Carotid intima-media thickness (cIMT) has been used as a surrogate marker for atherosclerosis and it has been shown to be an independent risk factor for CV disease. Our objective was to evaluate cIMT in HIV-infected patients on combined anti-retroviral therapy (cART) with and without lipodystrophy defined by fat mass ratio (L-FMR), and to determine the association of lipodystrophy and visceral obesity [(visceral (VAT), subcutaneous adipose tissue (SAT) volume and VAT/SAT ratio, objectively evaluated by CT scan] with cIMT.
Methods
Cross-sectional study of 199 HIV-infected patients. Body composition by DXA and abdominal CT, lipids, blood pressure, inflammatory markers, and cIMT by ultrasonography were performed. L-FMR was defined as the ratio of the percentage of trunk fat mass to the percentage of lower limb fat mass by DXA. Categorical variables were compared using the chi-square or Fisher’s exact test. Spearman correlation coefficients were estimated to study the association between cIMT and clinical and metabolic characteristics. Means of cIMT, adjusted for age, were calculated, using generalized linear models.
Results
L-FMR was present in 41.2% of patients and cIMT was higher in these patients [0.81 (0.24) vs. 0.76 (0.25); p = 0.037)]. Lipodystrophic patients had higher VAT and VAT/SAT ratio and lower SAT. cIMT was associated with lipodystrophy evaluated by FMR, trunk fat, total abdominal fat, VAT and VAT/SAT ratio. No association was observed between cIMT and leg fat mass. Using generalized linear models, cIMT means were adjusted for age and no significant differences remained after this adjustment. The adjusted mean of cIMT was 0.787 (95% CI: 0.751-0.823) in patients without lipodystrophy, and 0.775 (95% CI: 0.732-0.817) in those with lipodystrophy (p = 0.671).
Conclusions
HIV-infected patients on cART with lipodystrophy defined by FMR, had a significantly higher cIMT. Carotid IMT was also associated with classical cardiovascular risk factors. In these patients, visceral adipose tissue had a significant impact on cIMT, although age was the strongest associated factor.
doi:10.1186/1471-2334-14-348
PMCID: PMC4087129  PMID: 24958511
Lipodystrophy; HIV; Carotid intima media thickness; Fat mass ratio; Body composition
11.  Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection 
PLoS Medicine  2006;3(12):e492.
Background
Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection.
Methods and Findings
We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017).
Conclusions
These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.
HIV infection impairs the immune response to HCV. Even individuals who have cleared HCV infection remain at significant risk for a second episode of HCV viremia.
Editors' Summary
Background.
Because of shared transmission routes (contaminated needles, contaminated blood products, and, to a lesser extent, unprotected sex), a large proportion of HIV-infected individuals (estimates range between 25% and 33%) are also infected with the hepatitis C virus (HCV). In most but not all individuals infected with HCV, the virus infection is chronic and causes liver disease that can eventually lead to liver failure. Disease progress is slow; it often takes decades until infected individuals develop serious liver disease. In people infected with both HCV and HIV, however, liver disease caused by HCV often appears sooner and progresses faster. As highly active antiretroviral therapy (HAART) and prophylaxis of opportunistic infections increase the life span of persons living with HIV, HCV-related liver disease has become a major cause of hospital admissions and deaths among HIV-infected persons.
Why Was This Study Done?
A sizable minority of people who are infected with HCV manage to control the virus and never get liver disease, and scientists have found that these people somehow mounted a strong immune response against the hepatitis C virus. CD4+ T cells, the very immune cells that are infected and destroyed by HIV, play an important role in this immune response. The goal of the present study was to better understand how infection with HIV compromises the specific immune response to HCV and thereby the control of HCV disease progression.
What Did the Researchers Do and Find?
The researchers recruited four groups of patients, 94 in total, all of whom were infected with HCV. Two groups comprised patients who were infected with HIV as well as HCV, with either high or undetectable levels of HCV (30 patients in each group). The two other groups included patients not infected with HIV, either with high or undetectable levels of HCV (17 patients in each group). The researchers focused on the individuals who, despite coinfection with HIV, were able to control their HCV infection. They found that those individuals managed to maintain relatively high levels of CD4+ T cells that specifically recognize HCV. However, a quarter of these patients (six out of 25) failed to keep HCV levels down for the entire observation period of up to 2.5 years; their blood levels of HCV rose substantially, most likely due to recurrence of the previously suppressed virus (the researchers could not be certain that none of the patients had become infected again after a new exposure to HCV-contaminated blood, but there was no evidence that they had engaged in risky behavior). The rise of HCV levels in the blood of the relapsed patients coincided with a drop in overall CD4+ T cell numbers. Following relapse in these individuals, HCV did not return to undetectable levels during the study. During the same period none of the 16 HIV-uninfected people with controlled HCV infection experienced a recurrence of detectable HCV.
What Do These Findings Mean?
Despite the relatively small numbers of patients, these results suggest that recurrence of HCV after initial control of the virus is more likely in people who are coinfected with HIV, and that HCV control is lost when CD4+ T cell counts fall. This is one more reason to test all HIV-positive patients for HCV coinfection. Coinfected patients, even those who seem to be controlling HCV and would not automatically receive HCV treatment, should be regularly tested for a rise of HCV levels. In addition, maintaining CD4+ T cells at a high level might be particularly important for those patients, which means that doctors might consider starting HAART therapy earlier than is generally recommended for HIV-infected individuals. Additional studies are needed to support these recommendations, however, especially as this study did not follow the patients long enough to determine the consequences of the observed loss of control of HCV.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030492.
AIDS Treatment Data Network factsheet on HIV/HCV coinfection
US CDC factsheet on HIV/HCV coinfection
American Liver Foundation, information on HIV and HCV
MedlinePlus pages on HCV
doi:10.1371/journal.pmed.0030492
PMCID: PMC1705826  PMID: 17194190
12.  Hepatic Decompensation in Antiretroviral-Treated HIV/Hepatitis C-Coinfected Compared to Hepatitis C-Monoinfected Patients: A Cohort Study 
Annals of internal medicine  2014;160(6):369-379.
Background
The incidence and determinants of hepatic decompensation have been incompletely examined among HIV/hepatitis C virus (HCV)-coinfected patients in the antiretroviral therapy (ART) era, and few studies have compared rates of outcomes to those of patients with chronic HCV alone.
Objectives
To compare the incidence of hepatic decompensation between antiretroviral-treated HIV/HCV-coinfected and HCV-monoinfected patients, and evaluate factors associated with decompensation among coinfected patients on ART.
Design
Retrospective cohort study.
Setting
Veterans Health Administration.
Patients
4,280 HIV/HCV-coinfected patients who initiated ART and 6,079 HCV-monoinfected patients receiving care between 1997 and 2010. All patients had detectable HCV RNA and were HCV treatment-naïve.
Measurements
Incident hepatic decompensation, determined by diagnoses of ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage.
Results
The incidence of hepatic decompensation was greater among coinfected than monoinfected patients (at 10 years: 7.4% versus 4.8%; p<0.001). Compared to HCV-monoinfected patients, antiretroviral-treated HIV/HCV-coinfected patients had a higher rate of hepatic decompensation (hazard ratio [HR] accounting for competing risks, 1.56 [95% confidence interval (CI), 1.31–1.86]). Coinfected patients who maintained HIV RNA levels <1,000 copies/mL still had higher rates of decompensation than HCV-monoinfected patients (HR, 1.44 [95% CI, 1.05–1.99]). Baseline advanced hepatic fibrosis (FIB-4 >3.25; HR, 5.45 [95% CI, 3.79–7.84]), baseline hemoglobin <10 g/dL (HR, 2.24 [CI, 1.20–4.20]), diabetes mellitus (HR, 1.88[95% CI, 1.38–2.56]), and non-black race (HR, 2.12 [95% CI, 1.65–2.72]) were each associated with higher rates of decompensation among coinfected patients on ART.
Limitations
Observational study of predominantly male patients.
Conclusions
Despite ART, HIV/HCV-coinfected patients had higher rates of hepatic decompensation than HCV-monoinfected individuals. Rates of decompensation were higher for coinfected patients with advanced liver fibrosis, severe anemia, diabetes, and non-black race.
doi:10.7326/M13-1829
PMCID: PMC4254786  PMID: 24723077
hepatic decompensation; end-stage liver disease; HIV/HCV coinfection; HIV; hepatitis C
13.  Effectiveness of HCV core antigen and RNA quantification in HCV-infected and HCV/HIV-1-coinfected patients 
BMC Infectious Diseases  2014;14(1):577.
Background
The measurement of hepatitis C virus core antigen (HCV-coreAg) has been shown to be an indicator of active HCV infection. The aim of the present study was 1) to investigate the stability and effectiveness of HCV-coreAg and HCV-RNA quantification in HCV infection with or without HIV-1 coinfection, 2) to explore the association between the HCV-coreAg/HCV-RNA (Ag/RNA) ratio and the immune status in chronic HCV/HIV-1-coinfected patients.
Methods
A longitudinal investigation comprised of 227 HCV-monoinfected (n = 129) and HCV/HIV-1-coinfected (n = 98) patients was initiated in August 2009, and 139 (73 with HCV monoinfection and 66 with HCV/HIV-1 coinfection) were followed up in August 2012. Both HCV core antigen and HCV RNA quantification were determined on this cryopreserved plasma. HCV core antigen and HCV RNA quantification were performed subsequently. In addition, an in vitro experiment investigating the possibility of degradation of HCV components (core antigen and RNA) were conducted.
Results
Significant and stable correlations (p < 0.001) were observed both in chronic HCV-monoinfected and HCV/HIV-1-coinfected patients over the 3-year observation. Coinfected patients with immunocompromised condition had a significantly higher (p < 0.05) Ag/RNA ratios than those patients with immunocompetent condition both at two time points (2009 and 2012). Moreover, the Ag/RNA ratios were negatively correlated with CD4+ T-cell counts (p < 0.001). An in vitro experiment investigated the possibility of the slower degradation of HCV particles under HIV-related immunocompromised condition was conducted and the data demonstrated that the Ag/RNA ratios were significantly higher in HIV-1-positive plasma than in healthy plasma (p = 0.005) in this study.
Conclusions
Our longitudinal study indicated that the HCV-coreAg presented comparable dynamics over time as HCV RNA in chronic HCV-infected patients. Meanwhile, the HCV-coreAg/HCV-RNA ratio was closely associated with immune status in HCV/HIV-1-coinfected patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0577-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-014-0577-1
PMCID: PMC4225041  PMID: 25371245
CD4+ T-cell counts; Coinfection; HCV-coreAg; HCV-RNA; HCV/HIV-1; Ratio
14.  T-Cell Phenotypes, Apoptosis and Inflammation in HIV+ Patients on Virologically Effective cART with Early Atherosclerosis 
PLoS ONE  2012;7(9):e46073.
Objective
We investigated the potential relationship between T-cell phenotype, inflammation, endotoxemia, and atherosclerosis evaluated by carotid intima-media thickness (IMT) in a cohort of HIV-positive patients undergoing long-term virologically suppressive combination antiretroviral therapy (cART).
Design
We studied 163 patients receiving virologically suppressive cART.
Methods
We measured IMT (carotid ultrasound); CD4+/CD8+ T-cell activation (CD38, CD45R0), differentiation (CD127), apoptosis (CD95), and senescence (CD28, CD57) (flow cytometry); plasma sCD14, IL-6, TNF- α, sVCAM-1, hs-CRP, anti-CMV IgG (ELISA); LPS (LAL). The results were compared by Mann-Whitney, Kruskal-Wallis or Chi-square tests, and factors associated with IMT were evaluated by multivariable logistic regression.
Results
Of 163 patients, 112 demonstrated normal IMT (nIMT), whereas 51 (31.3%) had pathological IMT (pIMT: ≥1 mm). Of the patients with pIMT, 22 demonstrated an increased IMT (iIMT), and 29 were shown to have plaques. These patient groups had comparable nadir and current CD4+, VLs and total length of time on cART. Despite similar proportions of CD38-expressing CD8+ cells (p = .95), pIMT patients exhibited higher activated memory CD8+CD38+CD45R0+ cells (p = .038) and apoptotic CD4+CD95+ (p = .01) and CD8+CD95+ cells (p = .003). In comparison to nIMT patients, iIMT patients tended to have lower numbers of early differentiated CD28+CD57− memory CD4+ (p = .048) and CD28–CD57−CD8+ cells (p = .006), both of which are associated with a higher proliferative potential. Despite no differences in plasma LPS levels, pIMT patients showed significantly higher circulating levels of sCD14 than did nIMT patients (p = .046). No differences in anti-CMV IgG was shown. Although circulating levels of sCD14 seemed to be associated with a risk of ATS in an unadjusted analysis, this effect was lost after adjusting for classical cardiovascular predictors.
Conclusions
Despite the provision of full viral suppression by cART, a hyperactivated, pro-apoptotic T-cell profile characterizes HIV-infected patients with early vascular damage, for whom the potential contribution of subclinical endotoxemia and anti-CMV immunity should be investigated further.
doi:10.1371/journal.pone.0046073
PMCID: PMC3459872  PMID: 23029393
15.  Selected biochemical and hematological abnormalities in Nigerians with human immunodeficiency virus and hepatitis C virus coinfection 
Background
Liver disease has emerged as a major cause of morbidity and mortality in patients with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection, now that antiretroviral therapy has become more effective and has prolonged life expectancy in HIV-infected patients. The main objectives of this study were to determine the prevalence of HIV/HCV coinfection and the pattern of hematological and biochemical abnormalities associated with such dual infection.
Methods
In this study, patients with HIV infection (cases) were tested for anti-HCV antibodies. There was a control group made up of apparently healthy individuals who came to hospital for medical examination for various reasons. They also had an anti-HCV antibody test. Those who tested positive for anti-HCV antibodies among the cases and control subjects were further evaluated for hemoglobin concentration, total white cell count, platelet count, and liver function.
Results
One hundred and eighty HIV-infected patients and 180 control subjects participated in the study. The seroprevalence of anti-HCV antibodies in the HIV-infected patients and control subjects were 6.7% and 4.4%, respectively (P = 0.57). Serum total bilirubin, conjugated bilirubin, and alkaline phosphatase were significantly higher in the HIV/HCV coinfected patients compared with their HCV monoinfected counterparts (P = 0.0396, 0.0001, and 0.0016, respectively). The mean hemoglobin, white cell count, platelet count, and CD4+ T lymphocyte count were significantly lower in the HIV/HCV coinfected patients than the HCV monoinfected control group (P = 0.0082, 0.0133, 0.0031, and 0.0001, respectively).
Conclusion
The seroprevalence of anti-HCV antibodies in HIV-infected Nigerian patients is 6.7%. Patients with HIV/HCV coinfection have lower blood counts, higher serum bilirubin, and higher serum alkaline phosphatase compared with patients having HCV monoinfection.
doi:10.2147/HMER.S21735
PMCID: PMC3846592  PMID: 24367222
human immunodeficiency virus; hepatitis C virus; coinfection; biochemical; hematological abnormalities
16.  Markers of inflammation and CD8+ T-cell activation, but not monocyte activation are associated with subclinical carotid artery disease in HIV 
HIV medicine  2013;14(6):385-390.
OBJECTIVE
To explore the relationships between lymphocyte and monocyte activation, inflammation, and subclinical vascular disease among HIV-1 infected patients on antiretroviral therapy.
METHODS
Baseline mean common carotid artery (CCA) intima-media thickness (IMT) and carotid plaque (IMT >1.5cm) were evaluated in the first 60 subjects enrolled in the Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN in HIV (SATURN-HIV) trial. All subjects were adults, on stable ART with evidence of heightened T-cell activation (CD8+CD38+HLA-DR+ ≥19%) or increased inflammation (high sensitivity C-reactive protein ≥2mg/L). All had fasting LDL-cholesterol ≤130mg/dL.
RESULTS
78% were men and 65% African-American. Median (IQR) age and CD4+ count were 47(43,52) years and 648(511, 857) cells/µL, respectively. All had HIV-1 RNA<400 cps/mL. Mean CCA-IMT was correlated with log-transformed CD8+CD38+HLA-DR+% (r=0.326, p=0.043), interleukin-6 (r=0.283, p=0.028), soluble vascular cell adhesion molecule (sVCAM, r=0.434, p=0.004), tumor necrosis factor-α receptor-I (TNFR-I, r=0.591, p=<0.0001) and fibrinogen (r=0.257, p=0.047). After adjustment for traditional CVD risk factors, the association with TNFR-I (p=0.007) and fibrinogen (p=0.033) remained significant. Subjects with plaque (n=22, 37%) were older [51(7.7) vs. 43(9.4) years, mean(SD), p=0.002], had higher CD8+CD38+HLA-DR+% [31(24, 41) vs. 23(20,29)%, median(IQR), p=0.046] and higher sVCAM [737(159) vs. 592(160) ng/mL, p=0.008] compared to those without plaque. Pro-inflammatory monocyte subsets and serum markers of monocyte activation (soluble CD163 and soluble CD14) were not associated with CCA-IMT or plaque.
CONCLUSIONS
Participants in SATURN-HIV have a high level of inflammation and immune activation that is associated with subclinical vascular disease despite low serum LDL-C.
doi:10.1111/hiv.12013
PMCID: PMC3640592  PMID: 23332012
T-cell activation; Monocyte activation; Inflammation; Carotid intima-media thickness; Subclinical atherosclerosis
17.  Hepatitis C and the Risk of Kidney Disease and Mortality in Veterans With HIV 
Objectives
To examine the effect of hepatitis C virus (HCV) on the prevalence of chronic kidney disease (CKD) among veterans with HIV and to evaluate independent associations of HCV and CKD with mortality.
Methods
We studied a national cohort of HIV-infected patients receiving care through the Veterans Healthcare Administration from 1998 to 2004. CKD was defined as an estimated glomerular filtration rate [eGFR (mL/min/1.73 m2)] < 60. Poisson regression was used to assess relationships between CKD, HCV, and mortality.
Results
Among 23,155 HIV-infected veterans, 12% had CKD. Forty percent of the cohort was coinfected with HCV, and a higher proportion of coinfected subjects had CKD compared with monoinfected subjects (14% vs 11%, P < 0.001). During the median follow-up of 7.6 years, 37% of subjects died and a graduated increase in adjusted mortality rates occurred with lower levels of eGFR (P < 0.001). Adjusted mortality rates were consistently higher in HCV-coinfected subjects across all levels of eGFR (P < 0.001). HCV was independently associated with increased mortality (incidence rate ratio 1.23, 95% confidence interval 1.17–1.29).
Conclusions
CKD is prevalent in HIV-infected veterans and associated with substantially higher mortality. Compared with their monoinfected counterparts, veterans coinfected with HCV have significantly higher rates of CKD and mortality.
doi:10.1097/QAI.0b013e3181b980d4
PMCID: PMC3032564  PMID: 20104121
death; HIV; hepatitis C; kidney failure; veterans
18.  Association of HIV Infection, Hepatitis C Virus Infection, and Metabolic Factors With Liver Stiffness Measured by Transient Elastography 
The Journal of Infectious Diseases  2013;208(11):1776-1783.
Background. Few studies have examined the relationship of human immunodeficiency virus (HIV) monoinfection and its associated perturbations with liver fibrosis.
Methods. Using multivariable linear regression, we examined the demographic, behavioral, metabolic and viral factors associated with transient elastography–measured liver stiffness in 314 participants (165 HIV positive/hepatitis C virus [HCV] negative, 78 HIV positive/HCV positive, 14 HIV negative/HCV positive, 57 HIV negative/HCV negative) in the Women's Interagency HIV Study.
Results. Compared with HIV negative/HCV negative women, HIV positive/HCV positive women had higher median liver stiffness values (7.1 vs 4.4 kPa; P < .001); HIV positive/HCV negative and HIV negative/HCV negative women had similar liver stiffness values (both 4.4 kPa; P = .94). HIV/HCV coinfection remained associated with higher liver stiffness values (74% higher; 95% confidence interval [CI], 49–104) even after multivariable adjustment. Among HCV positive women, waist circumference (per 10-cm increase) was associated with 18% (95% CI, 7.5%–30%) higher liver stiffness values after multivariable adjustment; waist circumference showed little association among HIV positive/HCV negative or HIV negative/HCV negative women. Among HIV positive/HCV negative women, history of AIDS (13%; 95% CI, 4% –27%) and HIV RNA (7.3%; 95% CI, 1.59%–13.3%, per 10-fold increase) were associated with greater liver stiffness.
Conclusions. HCV infection but not HIV infection is associated with greater liver stiffness when infected women are compared with those with neither infection. Our finding that waist circumference, a marker of central obesity, is associated with greater liver stiffness in HIV/HCV-coinfected but not HIV-monoinfected or women with neither infection suggests that in the absence of HCV-associated liver injury the adverse effects of obesity are lessened.
doi:10.1093/infdis/jit357
PMCID: PMC3814832  PMID: 23901097
HIV; HCV; liver fibrosis; transient elastography; obesity; women
19.  The Effect of HIV Infection on Atherosclerosis and Lipoprotein Metabolism: a One Year Prospective Study 
Atherosclerosis  2013;229(1):206-211.
Objectives
HIV infection is associated with dyslipidaemia and increased risk of cardiovascular disease. The effects of HIV infection and antiretroviral treatment on surrogate markers of atherosclerosis, and lipoprotein metabolism were evaluated in a 12 month prospective study.
Methods and Results
Treatment-naive HIV patients were recruited into one of three groups: untreated HIV infection not likely to require initiation of antiretroviral therapy (ART) for at least 12 months; initiating treatment with non nucleoside reverse transcriptase inhibitor-containing ART regimen and initiating treatment with protease inhibitor-containing ART regimen. The patients underwent assessment of carotid intima-media thickness (cIMT), pulse wave velocity (PWV), brachial flow-mediated dilation (FMD) and variables of plasma lipoprotein metabolism at baseline and 12 months. The findings were compared with published values for age and sex matched HIV-negative healthy subjects in a cross-sectional fashion. cIMT and FMD were lower while PWV was higher in HIV-patients compared with HIV-negative individuals; none of the markers changed significantly during 12 months follow up. HIV patients had hypoalphalipoproteinemia and elevated plasma levels of lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein. The only significant changes in lipid-related variables were elevation of total cholesterol and triglycerides in patients treated with PI-containing regimen and elevation of plasma LCAT levels in patients treated with NNRTI-containing regimen. The ability of whole and apoB-depleted plasma to effect cholesterol efflux was not impaired in all three groups.
Conclusions
This study did not find evidence for rapid progression of subclinical atherosclerosis and deterioration of dyslipidaemia in HIV patients within 1 year.
doi:10.1016/j.atherosclerosis.2013.04.010
PMCID: PMC3691344  PMID: 23642913
HIV; atherosclerosis; lipoproteins; cholesterol metabolism
20.  Mortality of patients infected with HIV in the intensive care unit (2005 through 2010): significant role of chronic hepatitis C and severe sepsis 
Critical Care  2014;18(4):475.
Introduction
The combination antiretroviral therapy (cART) has led to decreased opportunistic infections and hospital admissions in human immunodeficiency virus (HIV)-infected patients, but the intensive care unit (ICU) admission rate remains constant (or even increased in some instances) during the cART era. Hepatitis C virus (HCV) infection is associated with an increased risk for hospital admission and/or mortality (particularly those related to severe liver disease) compared with the general population. The aim of this study was to assess the mortality among HIV-infected patients in ICU, and to evaluate the impact of HIV/HCV coinfection and severe sepsis on ICU mortality.
Methods
We carried out a retrospective study based on patients admitted to ICU who were recorded in the Minimum Basic Data Set (2005 through 2010) in Spain. HIV-infected patients (All-HIV-group (n = 1,891)) were divided into two groups: HIV-monoinfected patients (HIV group (n = 1,191)) and HIV/HCV-coinfected patients (HIV/HCV group (n = 700)). A control group (HIV(-)/HCV(-)) was also included (n = 7,496).
Results
All-HIV group had higher frequencies of severe sepsis (57.7% versus 39.4%; P < 0.001) than did the control group. Overall, ICU mortality in patients with severe sepsis was much more frequent than that in patients without severe sepsis (other causes) at days 30 and 90 in HIV-infected patients and the control group (P < 0.001). Moreover, the all-HIV group in the presence or absence of severe sepsis had a higher percentage of death than did the control group at days 7 (P < 0.001), 30 (P < 0.001) and 90 (P < 0.001). Besides, the HIV/HCV group had a higher percentage of death, both in patients with severe sepsis and in patients without severe sepsis compared with the HIV group at days 7 (P < 0.001) and 30 (P < 0.001), whereas no differences were found at day 90. In a bayesian competing-risk model, the HIV/HCV group had a higher mortality risk (adjusted hazard ratio (aHR) = 1.44 (95% CI = 1.30 to 1.59) and aHR = 1.57 (95% CI = 1.38 to 1.78) for patients with and without severe sepsis, respectively).
Conclusions
HIV infection was related to a higher frequency of severe sepsis and death among patients admitted to the ICU. Besides, HIV/HCV coinfection contributed to an increased risk of death in both the presence and the absence of severe sepsis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0475-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-014-0475-3
PMCID: PMC4176576  PMID: 25159592
21.  Effects of Aging and Smoking on Carotid Intima Media Thickness in HIV-infection 
AIDS (London, England)  2013;27(1):49-57.
Objectives
To investigate the effects of aging and smoking on carotid intima-media thickness (cIMT) among patients with and without HIV.
Methods
Data from a community sample of HIV-infected and HIV-uninfected participants were analyzed. Carotid intima-media thickness was measured via carotid ultrasound and smoking history was obtained via patient interview.
Results
Data on 166male and female participants with stable HIV-infection and 152 healthy HIV-uninfected participants were analyzed. Among the HIV-infected and HIV-uninfected participants, a significant association was observed between age and cIMT [r=0.51, P<0.0001 (HIV), r=0.39, P<0.0001, (non-HIV)], and between smoking burden and cIMT [r=0.42, P<0.0001 (HIV), r=0.24, P=0.003 (non-HIV)]. In multivariate regression modeling among all participants (HIV and non-HIV), a significant three-way interaction was observed between age, smoking burden, and HIV status with respect to cIMT (P<0.010), controlling for gender, race and traditional cardiovascular disease (CVD) risk factors, such that increased cIMT was associated with increased smoking burden and age to a greater degree among HIV-infected vs. HIV-uninfected participants. Among HIV-infected participants a significant interaction between smoking burden and age with respect to cIMT was seen (P=0.027), controlling for race, gender, CVD risk factors, immunological function and antiretroviral therapy use.
Conclusion
A significant interaction between HIV, age and smoking on cIMT was observed, suggesting that HIV-infection modifies the relationship of age and smoking on cIMT in this population. These findings emphasize the need to encourage smoking cessation in this population, due to its deleterious effect on subclinical atherosclerosis in older HIV-infected patients.
doi:10.1097/QAD.0b013e328358b29c
PMCID: PMC3690796  PMID: 22874518
HIV; Aging; Cardiovascular Diseases; Smoking
22.  Coinfection with HIV-1 Alleviates Iron Accumulation in Patients with Chronic Hepatitis C Virus Infection 
PLoS ONE  2014;9(6):e98039.
Most chronically-infected hepatitis C virus (HCV) patients have increased levels of iron in the liver. Iron overload reduces sustained responses to antiviral therapy, leading to more rapid progression to liver cirrhosis and the development of hepatocellular carcinoma. However, it is still unclear how HIV-1 infection affects iron status in patients chronically infected with HCV. The present study recruited 227 patients from a village in central China. These patients were either monoinfected with HCV (n = 129) or coinfected with HCV/HIV-1 (n = 98). Healthy controls (n = 84) were also recruited from the same village. Indicators of iron status, such as serum levels of iron, ferritin, and transferrin, total iron-binding capacity (TIBC), transferrin saturation (Tfs), and hepcidin, were analyzed and compared across the three groups. The results showed that serum levels of iron (p = 0.001) and ferritin (p = 0.009) and the Tfs (p = 0.002) were significantly higher in HCV-monoinfected patients than in the healthy controls; however, there were no differences in iron levels and Tfs between HCV/HIV-1 coinfected patients and healthy controls. Additionally, although serum hepcidin levels in HCV-monoinfected and HCV/HIV-1-coinfected patients were lower (p<0.001) than those in health controls, the levels in coinfected patients were higher (p = 0.025) than those in HCV-monoinfected patients. Serum iron and ferritin levels in HCV-monoinfected patients were positively correlated with serum ALT/AST. Serum transferrin levels were negatively correlated with ALT/AST levels. The levels of iron in the serum of coinfected patients with a CD4+T-cell count <500/µl were lower than those in patients with a CD4+T-cell count ≥500/µl, whereas serum hepcidin levels showed the opposite trend. Taken together, these results suggest that coinfection with HIV-1 alleviates iron accumulation caused by chronic HCV infection. Our study indicated that determining the status of serum iron and other iron-associated parameters will be helpful to understand the complexity of alternations in iron distribution in HCV/HIV-1-coinfected patients.
doi:10.1371/journal.pone.0098039
PMCID: PMC4057081  PMID: 24927015
23.  Vitamin D Levels and Markers of Arterial Dysfunction in HIV 
Abstract
HIV-infected patients have low vitamin D levels as well as an increase in cardiovascular (CVD) risk. We examined the relationship between vitamin D and three markers of arterial dysfunction among HIV-infected individuals on stable antiretroviral (ARV) therapy. Levels of 25-hydroxyvitamin D [25(OH)D] were assessed by chemiluminescent immunoassay (DiaSorin) in 100 enrollees into the Hawaii Aging with HIV-Cardiovascular Cohort Study, a cohort of HIV-infected subjects age ≥40 years on stable (≥6 months) ARV therapy. The relationships between 25(OH)D levels and brachial artery flow-mediated dilation (FMD), right common carotid artery intima-media thickness (cIMT), and coronary artery calcium (CAC) were examined. Analytical methods included Pearson's correlations, Kruskal–Wallis tests, relative risks, and linear regression models. The cohort was 86% male and 60% white with a median age of 52 years and CD4 of 510 cells/mm3. The median (Q1, Q3) level of 25(OH)D was 27.9 ng/ml (21.8, 38.3). There were 72 FMD, 50 cIMT, and 90 CAC measurements available for analyses. A significant correlation was observed between 25(OH)D levels and FMD (r=0.30, p=0.01) but not with cIMT (r=−0.05, p=0.76). In a linear regression model, Framingham risk score attenuated the relationship between FMD and 25(OH)D. Those with lower 25(OH)D levels were at slightly higher risk of having CAC (RR=1.02, p=0.04). Among those with CAC, lower 25(OH)D levels were not associated with higher CAC scores (p=0.36). Lower vitamin D levels are associated with evidence of subclinical arterial dysfunction in HIV-infected individuals. The significance of these findings warrants further investigation.
doi:10.1089/aid.2011.0086
PMCID: PMC3399561  PMID: 21978287
24.  A Comparison of Treatment Eligibility for Hepatitis C Virus in HCV-Monoinfected Versus HCV/HIV-Coinfected Persons in Electronically Retrieved Cohort of HCV-Infected Veterans 
Abstract
Treatment rates for hepatitis C virus (HCV) are low in actual clinical settings. However, the proportion of patients eligible for treatment, especially among those coinfected with HIV, is not well known. Our aim was to determine and compare the rates for HCV treatment eligibility among HCV and HCV-HIV-coinfected persons. We assembled a national cohort of HCV-infected veterans in care from 1998–2003, using the VA National Patient Care Database for demographic/clinical information, the Pharmacy Benefits Management database for pharmacy records, and the Decision Support Systems database for laboratory data. We compared the HCV-monoinfected and HCV-HIV-coinfected subjects for treatment indications and eligibility using current treatment guidelines. Of the 27,452 subjects with HCV and 1225 with HCV-HIV coinfection, 74.0% and 84.6% had indications for therapy and among these, 43.9% of HCV-monoinfected and 28.4% of HCV-HIV-coinfected subjects were eligible for treatment. Anemia, decompensated liver disease (DLD), chronic obstructive pulmonary disease (COPD), recent alcohol abuse, and coronary artery disease were the most common contraindications in the HCV, and anemia, DLD, renal failure, recent drug abuse, and COPD in the HCV-HIV-coinfected group. Among those eligible for treatment, only 23% of the HCV-monoinfected and 15% of the HCV-HIV-coinfected subjects received any treatment for HCV. Most veterans with HCV are not eligible for treatment according to the current guidelines. Even for those who are eligible for treatment, only a minority is prescribed treatment. Several contraindications are modifiable and aggressive management of those may improve treatment prescription rates.
doi:10.1089/aid.2011.0004
PMCID: PMC3719436  PMID: 21338329
25.  CIHR Canadian HIV Trials Network Co-Infection and Concurrent Diseases Core: Updated Canadian guidelines for the treatment of hepatitis C infection in HIV-hepatitis C coinfected adults 
Treatment of HIV-hepatitis C virus (HCV)-coinfected individuals is considerably more complex than the treatment of monoinfected individuals, due to several factors including interactions among medications and accelerated progression of liver disease. Since the first Canadian guidelines for the treatment of HIV-HCV coinfected patients were published in the Winter 2013 issue of the Journal, several new medications that show considerable promise for the treatment of HCV have become available in Canada. Thus, the authors provide an update to the 2013 guidelines and include updated recommendations for treatment that incorporate these new medications.
BACKGROUND:
Hepatitis C virus (HCV) coinfection occurs in 20% to 30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Management of HIV-HCV coinfection is more complex due to the accelerated progression of liver disease, the timing and nature of antiretroviral and HCV therapy, mental health and addictions management, socioeconomic obstacles and drug-drug interactions between new HCV direct-acting antiviral therapies and antiretroviral regimens.
OBJECTIVE:
To update national standards for the management of HCV-HIV coinfected adults in the Canadian context.
METHODS:
A standing working group with specific clinical expertise in HIV-HCV coinfection was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published data regarding HCV antiviral treatments and to update the Canadian HIV-HCV coinfection guidelines.
RESULTS:
Recent data suggest that the gap in sustained virological response rates between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All HIV-HCV coinfected individuals should be assessed for HCV therapy. First-line treatment for genotypes 1 through 6 includes pegylated interferon and weight-based ribavirin dosing plus the nucleotide sofosbuvir for 12 weeks. Sofosbuvir in combination with the protease inhibitor simeprevir is another first-line consideration for genotype 1 infection. Sofosbuvir with ribavirin for 12 weeks (genotype 2) and 24 weeks (genotype 3) is also recommended as first-line treatment.
DISCUSSION:
Recommendations may not supersede individual clinical judgement.
PMCID: PMC4277159  PMID: 25587293
Antivirals; Coinfection; HCV; HIV; Treatment; Updated guidelines

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