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Review of the neurological aspects of HIV infection. J Neurol Sci 2021; 425:117453. [PMID: 33895464 DOI: 10.1016/j.jns.2021.117453] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 04/12/2021] [Accepted: 04/12/2021] [Indexed: 11/20/2022]
Abstract
There are almost 40 million people in the world who live with the human immunodeficiency virus (HIV). The neurological manifestations associated with HIV contribute to significant morbidity and mortality despite the advances made with anti-retroviral therapy (ART). This review presents an approach to classification of neurological disorders in HIV, differentiating diseases due to the virus itself and those due to opportunistic infection. The effects of antiretroviral therapy are also discussed. The emphasis is on the developing world where advanced complications of HIV itself and infections such as tuberculosis (TB), toxoplasmosis and cryptococcal meningitis remain prevalent.
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Guaraldi G, Raggi P. Antiretroviral therapies and cardiovascular risk: True or false? Atherosclerosis 2017; 263:313-314. [DOI: 10.1016/j.atherosclerosis.2017.05.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 05/23/2017] [Indexed: 10/19/2022]
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Shahbaz S, Manicardi M, Guaraldi G, Raggi P. Cardiovascular disease in human immunodeficiency virus infected patients: A true or perceived risk? World J Cardiol 2015; 7:633-44. [PMID: 26516417 PMCID: PMC4620074 DOI: 10.4330/wjc.v7.i10.633] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 09/07/2015] [Accepted: 09/16/2015] [Indexed: 02/06/2023] Open
Abstract
After the successful introduction of highly active antiretroviral agents the survival of patients infected with the human immunodeficiency virus (HIV) in developed countries has increased substantially. This has allowed the surfacing of several chronic diseases among which cardiovascular disease (CVD) is prominent. The pathogenesis of CVD in HIV is complex and involves a combination of traditional and HIV related factors. An accurate assessment of risk of CVD in these patients is still elusive and as a consequence the most appropriate preventive and therapeutic interventions remain controversial.
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Affiliation(s)
- Shima Shahbaz
- Shima Shahbaz, Paolo Raggi, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton T6G 2B7, Alberta, Canada
| | - Marcella Manicardi
- Shima Shahbaz, Paolo Raggi, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton T6G 2B7, Alberta, Canada
| | - Giovanni Guaraldi
- Shima Shahbaz, Paolo Raggi, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton T6G 2B7, Alberta, Canada
| | - Paolo Raggi
- Shima Shahbaz, Paolo Raggi, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton T6G 2B7, Alberta, Canada
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van den Dries LWJ, Gruters RA, Hövels-van der Borden SBC, Kruip MJHA, de Maat MPM, van Gorp ECM, van der Ende ME. von Willebrand Factor is elevated in HIV patients with a history of thrombosis. Front Microbiol 2015; 6:180. [PMID: 25814984 PMCID: PMC4356086 DOI: 10.3389/fmicb.2015.00180] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 02/19/2015] [Indexed: 11/21/2022] Open
Abstract
Background: Arterial and venous thrombotic events are more prevalent in HIV infected individuals compared to the general population, even in the era of combination antiretroviral therapy. Although the mechanism is not fully understood, recent evidence suggests a role for chronic immune activation. Methods: We reviewed the Dutch National HIV registry database for HIV infected patients in Rotterdam with a history of arterial or venous thrombosis and calculated the incidence. We collected samples from patients with and without thrombosis and compared plasma levels of lipopolysaccharide (LPS), LPS binding protein (LBP), soluble CD14 (sCD14), and von Willebrand Factor antigen level (vWF). Results: During a 10-year period, a total of 60 documented events in 14,026 person years of observation (PYO) occurred, resulting in an incidence rate of 2.50, 2.21, and 4.28 for arterial, venous and combined thrombotic events per 1000 PYO, respectively. The vWF was elevated in the majority of study subjects (mean 2.36 SD ± 0.88 IU/ml); we found a significant difference when comparing venous cases to controls (mean 2.68 SD ± 0.82 IU/ml vs. 2.20 SD ± 0.77 IU/ml; p = 0.024). This difference remained significant for recurrent events (mean 2.78 SD ± 0.75; p = 0.043). sCD14 was positively correlated with LPS (r = 0.255; p = 0.003). Conclusion: The incidence of venous thrombosis was two-fold higher in HIV infected patients compared to age-adjusted data from general population cohort studies. We couldn't find a clear association between immune activation markers to either arterial or venous thrombotic events. We observed a marked increase in vWF levels as well as a correlation of vWF to first and recurrent venous thrombo-embolic events. These findings suggest that HIV infection is an independent risk factor for coagulation abnormalities and could contribute to the observed high incidence in venous thrombosis. This could be a reason to prolong anti-thrombotic treatment in HIV patients with a history of thrombosis.
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Affiliation(s)
| | - Rob A Gruters
- Department of Viroscience, Erasmus MC, University Medical Center Rotterdam, Netherlands
| | | | - Marieke J H A Kruip
- Division of Hematology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Netherlands
| | - Moniek P M de Maat
- Division of Hematology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Netherlands
| | - Eric C M van Gorp
- Department of Viroscience, Erasmus MC, University Medical Center Rotterdam, Netherlands ; Division of Infectious Diseases, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Netherlands
| | - Marchina E van der Ende
- Division of Infectious Diseases, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Netherlands
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Enfermedad arterial periférica e infección por virus inmunodeficiencia humana. ANGIOLOGIA 2011. [DOI: 10.1016/j.angio.2011.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Bloomfield GS, Hogan JW, Keter A, Sang E, Carter EJ, Velazquez EJ, Kimaiyo S. Hypertension and obesity as cardiovascular risk factors among HIV seropositive patients in Western Kenya. PLoS One 2011; 6:e22288. [PMID: 21779407 PMCID: PMC3136516 DOI: 10.1371/journal.pone.0022288] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Accepted: 06/21/2011] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND There is increased risk of cardiovascular disease among HIV seropositive individuals. The prevalence of HIV is highest in sub-Saharan Africa; however, HIV-related cardiovascular risk research is largely derived from developed country settings. Herein, we describe the prevalence of hypertension and obesity in a large HIV treatment program in Kenya. METHODS We performed a retrospective analysis of the electronic medical records of a large HIV treatment program in Western Kenya between 2006 and 2009. We calculated the prevalence of hypertension and obesity among HIV+ adults as well as utilized multiple logistic regression analyses to examine the relationship between clinical characteristics, HIV-related characteristics, and hypertension. RESULTS Our final sample size was 12,194. The median systolic/diastolic blood pressures were similar for both sexes (male: 110/70 mmHg, female: 110/70 mmHg). The prevalence of hypertension among men and women were 11.2% and 7.4%, respectively. Eleven percent of men and 22.6% of women were overweight/obese (body mass index ≥25 kg/m(2)). Ordinal logistic regression analyses showed that overweight/obesity was more strongly associated with hypertension among HIV+ men (OR 2.41, 95% CI 1.88-3.09) than a higher successive age category (OR 1.62, 95% CI 1.40-1.87 comparing 16-35, 36-45 and >45 years categories). Among women, higher age category and overweight/obesity were most strongly associated with hypertension (age category: OR 2.21, 95% CI 1.95-2.50, overweight/obesity: OR 1.80, 95% CI 1.50-2.16). Length of time on protease inhibitors was not found to be related to hypertension for men (OR 1.62, 95% CI 0.42-6.20) or women (OR 1.17, 95% CI 0.37-2.65) after adjustment for CD4 count, age and BMI. CONCLUSION In Western Kenya, there is a high prevalence of hypertension and overweight/obesity among HIV+ patients with differences observed between men and women. The care of HIV+ patients in sub-Saharan Africa should also include both identification and management of associated cardiovascular risk factors.
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Affiliation(s)
- Gerald S Bloomfield
- Division of Cardiology and Duke Clinical Research Institute, Duke University, Durham, North Carolina, United States of America.
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Kaposi’s sarcoma-associated herpesvirus infection of endothelial progenitor cells impairs angiogenic activity in vitro. J Microbiol 2011; 49:299-304. [DOI: 10.1007/s12275-011-0408-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Accepted: 11/29/2010] [Indexed: 10/18/2022]
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8
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Annamalai L, Westmoreland SV, Domingues HG, Walsh DG, Gonzalez RG, O'Neil SP. Myocarditis in CD8-depleted SIV-infected rhesus macaques after short-term dual therapy with nucleoside and nucleotide reverse transcriptase inhibitors. PLoS One 2010; 5:e14429. [PMID: 21203448 PMCID: PMC3009713 DOI: 10.1371/journal.pone.0014429] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Accepted: 11/08/2010] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Although highly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV infection, a number of antiretroviral toxicities have been described, including myocardial toxicity resulting from the use of nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs). Current treatment guidelines recommend the use of HAART regimens containing two NRTIs for initial therapy of HIV-1 positive individuals; however, potential cardiotoxicity resulting from treatment with multiple NRTIs has not been addressed. METHODOLOGY/PRINCIPAL FINDINGS We examined myocardial tissue from twelve CD8 lymphocyte-depleted adult rhesus macaques, including eight animals infected with simian immunodeficiency virus, four of which received combined antiretroviral therapy (CART) consisting of two NRTIs [(9-R-2-Phosphonomethoxypropyl Adenine) (PMPA) and (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine (RCV)] for 28 days. Multifocal infiltrates of mononuclear inflammatory cells were present in the myocardium of all macaques that received CART, but not untreated SIV-positive animals or SIV-negative controls. Macrophages were the predominant inflammatory cells within lesions, as shown by immunoreactivity for the macrophage markers Iba1 and CD68. Heart specimens from monkeys that received CART had significantly lower virus burdens than untreated animals (p<0.05), but significantly greater quantities of TNF-α mRNA than either SIV-positive untreated animals or uninfected controls (p<0.05). Interferon-γ (IFN-γ), IL-1β and CXCL11 mRNA were upregulated in heart tissue from SIV-positive monkeys, independent of antiretroviral treatment, but CXCL9 mRNA was only upregulated in heart tissue from macaques that received CART. CONCLUSIONS/SIGNIFICANCE These results suggest that short-term treatment with multiple NRTIs may be associated with myocarditis, and demonstrate that the CD8-depleted SIV-positive rhesus monkey is a useful model for studying the cardiotoxic effects of combined antiretroviral therapy in the setting of immunodeficiency virus infection.
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Affiliation(s)
- Lakshmanan Annamalai
- Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America
| | - Susan V. Westmoreland
- Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America
- * E-mail:
| | - Heber G. Domingues
- Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America
| | - Dennis G. Walsh
- Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America
| | - R. Gilberto Gonzalez
- Neuroradiology, Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America
| | - Shawn P. O'Neil
- Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America
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Guaraldi G, Stentarelli C, Zona S, Orlando G, Carli F, Ligabue G, Lattanzi A, Zaccherini G, Rossi R, Modena MG, Alexopoulos N, Palella F, Raggi P. Lipodystrophy and anti-retroviral therapy as predictors of sub-clinical atherosclerosis in human immunodeficiency virus infected subjects. Atherosclerosis 2010; 208:222-7. [DOI: 10.1016/j.atherosclerosis.2009.06.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Revised: 05/29/2009] [Accepted: 06/08/2009] [Indexed: 02/04/2023]
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Galati V, Grilli E, Sallustio F, Petrosillo N. An adult HIV patient with unilateral Moyamoya syndrome. Clin Neurol Neurosurg 2010; 112:76-8. [DOI: 10.1016/j.clineuro.2009.09.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2009] [Revised: 08/30/2009] [Accepted: 09/06/2009] [Indexed: 10/20/2022]
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Chen L, Jarujaron S, Wu X, Sun L, Zha W, Liang G, Gurley EC, Studer EJ, Hylemon PB, Pandak WM, Zhang L, Wang G, Li X, Dent P, Zhou H. HIV protease inhibitor lopinavir-induced TNF-alpha and IL-6 expression is coupled to the unfolded protein response and ERK signaling pathways in macrophages. Biochem Pharmacol 2009; 78:70-7. [PMID: 19447225 PMCID: PMC2704357 DOI: 10.1016/j.bcp.2009.03.022] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2009] [Revised: 03/17/2009] [Accepted: 03/19/2009] [Indexed: 01/05/2023]
Abstract
HIV protease inhibitor (PI)-associated cardiovascular risk, especially atherosclerosis, has become a major concern in the clinic. Macrophages are key players in the inflammatory response and atherosclerosis formation. We have previously shown that HIV PIs induce endoplasmic reticulum (ER) stress, activate the unfolded protein response (UPR), and increase the synthesis of the inflammatory cytokines, TNF-alpha and IL-6, by regulating the intracellular translocation of RNA binding protein HuR in macrophages. However, the underlying signaling mechanisms remain unclear. We show here that the HIV PI lopinavir significantly activated the extracellular-signal regulated protein kinase (ERK), but not c-Jun N-terminal kinase (JNK) and p38 MAPK. Lopinavir-induced cytosolic translocation of HuR and TNF-alpha and IL-6 synthesis was attenuated by specific chemical inhibitor of MEK (PD98058) or over-expression of dominant negative mutant of MEK1. In addition, we demonstrated that lopinavir-induced ERK activation and TNF-alpha and IL-6 expression were completely inhibited in macrophages from CHOP null mice. Taken together, these results indicate activation of the UPR plays an essential role in HIV PI-induced inflammatory cytokine synthesis and release by activating ERK, which increases the cytosolic translocation of HuR and subsequent binding to the 3'UTR of TNF-alpha and IL-6 mRNAs in macrophages.
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Affiliation(s)
- Li Chen
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Sirikalaya Jarujaron
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Xudong Wu
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Lixin Sun
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Weibin Zha
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Guang Liang
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Emily C. Gurley
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Elaine J. Studer
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Phillip B. Hylemon
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - William M. Pandak
- Department of Internal Medicine/Gastroenterology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Luyong Zhang
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Guangji Wang
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Xiaokun Li
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Paul Dent
- Department of Biochemistry, Virginia Commonwealth University, Richmond, VA, USA, 23298
| | - Huiping Zhou
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA, 23298
- Department of Internal Medicine/Gastroenterology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA, USA, 23298
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A genetic polymorphism of matrix metalloproteinase 9 (MMP-9) affects the changes in circulating MMP-9 levels induced by highly active antiretroviral therapy in HIV patients. THE PHARMACOGENOMICS JOURNAL 2009; 9:265-73. [DOI: 10.1038/tpj.2009.13] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Rosenkranz SL, Yarasheski KE, Para MF, Reichman RC, Morse GD. Antiretroviral Drug Levels and Interactions Affect Lipid, Lipoprotein, and Glucose Metabolism in HIV-1 Seronegative Subjects: A Pharmacokinetic-Pharmacodynamic Analysis. Metab Syndr Relat Disord 2007; 5:163-73. [PMID: 18007962 PMCID: PMC2078603 DOI: 10.1089/met.2006.0034] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND HIV-infected patients treated with antiretroviral medications (ARVs) develop undesirable changes in lipid and glucose metabolism that mimic the metabolic syndrome and may be proatherogenic. Antiretroviral drug levels and their interactions may contribute to these metabolic alterations. METHODS Fifty six HIV-seronegative adults were enrolled in an open-label, randomized, pharmacokinetic interaction study, and received a nonnucleoside reverse transcriptase inhibitor (efavirenz on days 1-21) plus a protease inhibitor (PI; amprenavir on days 11-21), with a second PI on days 15-21 (saquinavir, nelfinavir, indinavir, or ritonavir). Fasting triglycerides, total LDL-and HDL-cholesterol, glucose, insulin, and C-peptide levels were measured on days 0, 14, 21, and 2-3 weeks after discontinuing drugs. Regression models were used to estimate changes in these parameters and associations between these changes and circulating levels of study drugs. RESULTS Short-term efavirenz and amprenavir administration significantly increased cholesterol, triglycerides, and glucose levels. Addition of a second protease inhibitor further increased triglycerides, total and LDL-cholesterol levels. Higher amprenavir levels predicted larger increases in triglycerides, total, and LDL-cholesterol. Two weeks after all study drugs were stopped, total, LDL-, and HDL-cholesterol remained elevated above baseline. CONCLUSIONS ARV regimens that include a nonnucleoside reverse transcriptase inhibitor plus single or boosted PIs are becoming more common, but the pharmacodynamic interactions associated with these regimens can result in persistent, undesirable alterations in serum lipid/lipoprotein levels. Additional pharmacodynamic studies are needed to examine the metabolic effects of ritonavir-boosted regimens, with and without efavirenz.
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Obel N, Thomsen HF, Kronborg G, Larsen CS, Hildebrandt PR, Sørensen HT, Gerstoft J. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis 2007; 44:1625-31. [PMID: 17516408 DOI: 10.1086/518285] [Citation(s) in RCA: 258] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2006] [Accepted: 02/18/2007] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND There are concerns about highly active antiretroviral therapy (HAART) causing a progressive increase in the risk of ischemic heart disease. We examined this issue in a nationwide cohort study of patients with human immunodeficiency virus (HIV) infection and a population-based control group. METHODS We determined the rate of first hospitalization for ischemic heart disease in all Danish patients with HIV infection (3953 patients) from 1 January 1995 through 31 December 2004 and compared this rate with that for 373,856 subjects in a population-based control group. Data on first hospitalization for ischemic heart disease and comorbidity were obtained from the Danish National Hospital Registry for all study participants. We used Cox's regression to compute the hospitalization rate ratio as an estimate of relative risk, adjusting for comorbidity. RESULTS Although the difference was not statistically significant, patients with HIV infection who had not initiated HAART were slightly more likely to be hospitalized for the first time with ischemic heart disease than were control subjects (adjusted relative risk, 1.39; 95% confidence interval, 0.81-2.33). After HAART initiation, the risk increase became substantially higher (adjusted relative risk, 2.12; 95% confidence interval, 1.62-2.76), but the relative risk did not further increase in the initial 8 years of HAART. CONCLUSIONS Compared with the general population, HIV-infected patients receiving HAART have an increased risk of ischemic heart disease, but the relative risk is stable up to 8 years after treatment initiation.
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Affiliation(s)
- Niels Obel
- Department of Infectious Diseases, Rigshospitalet, Hvidovre, Denmark.
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Pedrol-Clotet E, Deig-Comerma E, Ribell-Bachs M, Vidal-Castell I, García-Rodríguez P, Soler A. [Bupropion use for smoking cessation in HIV-infected patients receiving antiretroviral therapy]. Enferm Infecc Microbiol Clin 2007; 24:509-11. [PMID: 16987469 DOI: 10.1157/13092468] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Smoking is the most important modifiable cardiovascular risk factor. Bupropion administration is an effective method to achieve smoking cessation (SC), but the drug is metabolized by the cytochrome P450 enzyme system and this might cause interactions with antiretroviral drugs. We present a prospective study of bupropion SC therapy in HIV-positive patients under antiretroviral treatment. A total of 21 patients were studied; 38% of them stopped smoking for more than one year. No clinically significant drug interactions were found. Bupropion SC therapy was effective in HIV-positive patients and did not cause significant clinical interactions with antiretroviral drugs.
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Affiliation(s)
- Enric Pedrol-Clotet
- Unidad de Enfermedades Infecciosas-VIH, Hospital General de Granollers, Barcelona, España.
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Abstract
The use of highly active antiretroviral therapy (HAART) has resulted in sustained reductions in mortality from HIV infection. In recent years, HAART has also been associated with metabolic complications that may increase patients' cardiovascular disease risk. Recent studies have begun to support a more complex interaction between HAART, HIV infection itself, and other traditional social and immunologic factors that may predispose patients to premature cardiovascular disease. Substantial progress has been made in the development of newer antiretroviral therapies that have a better metabolic profile with respect to dyslipidemia, hyperglycemia, and lipodystrophy. Optimal selection of metabolically neutral antiretroviral therapies, together with aggressive management of other modifiable coronary risk factors, may improve cardiovascular disease risk in the long term.
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Affiliation(s)
- Kristin Mondy
- Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
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Sterne JAC, May M, Bucher HC, Ledergerber B, Furrer H, Cavassini M, Bernasconi E, Hirschel B, Egger M, Swiss HIV Cohort. HAART and the heart: changes in coronary risk factors and implications for coronary risk in men starting antiretroviral therapy. J Intern Med 2007; 261:255-67. [PMID: 17305648 DOI: 10.1111/j.1365-2796.2006.01761.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To estimate changes in coronary risk factors and their implications for coronary heart disease (CHD) rates in men starting highly active antiretroviral therapy (HAART). METHODS Men participating in the Swiss HIV Cohort Study with measurements of coronary risk factors both before and up to 3 years after starting HAART were identified. Fractional polynomial regression was used to graph associations between risk factors and time on HAART. Mean risk factor changes associated with starting HAART were estimated using multilevel models. A prognostic model was used to predict corresponding CHD rate ratios. RESULTS Of 556 eligible men, 259 (47%) started a nonnucleoside reverse transcriptase inhibitor (NNRTI) and 297 a protease inhibitor (PI) based regimen. Levels of most risk factors increased sharply during the first 3 months on HAART, then more slowly. Increases were greater with PI- than NNRTI-based HAART for total cholesterol (1.18 vs. 0.98 mmol L(-1)), systolic blood pressure (3.6 vs. 0 mmHg) and BMI (1.04 vs. 0.55 kg m(2)) but not HDL cholesterol (0.24 vs. 0.32 mmol L(-1)) or glucose (1.02 vs. 1.03 mmol L(-1)). Predicted CHD rate ratios were 1.40 (95% CI 1.13-1.75) and 1.17 (0.95-1.47) for PI- and NNRTI-based HAART respectively. CONCLUSIONS Coronary heart disease rates will increase in a majority of patients starting HAART: however the increases corresponding to typical changes in risk factors are relatively modest and could be offset by lifestyle changes.
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Affiliation(s)
- J A C Sterne
- Department of Social Medicine, University of Bristol, Bristol, UK
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18
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Abstract
Highly active antiretroviral therapy (HAART) has significantly improved the prognosis of patients with HIV infection; however, the use of protease inhibitors has been associated with increased cardiovascular events and worsening of multiple coronary heart disease risk factors including dyslipidemia, insulin resistance, and endothelial dysfunction. Endothelial dysfunction may be caused by the infection itself, the immunologic responses due to the HIV virus, and also by the effects of HAART through their effects on both lipid and glucose metabolism. The study of endothelial function in HIV infection and its modifications by HAART is an exciting new field in clinical research, limited by multiple factors such as viral factors, immunologic conditions, and metabolic drug effects that could affect the interpretation of endothelial impairment. Further studies are still needed to understand the significance of endothelial dysfunction in the cardiovascular risk assessment of patients with HIV infection.
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Affiliation(s)
- Bruno R Cotter
- University of California San Diego Medical Center, 200 West Arbor Street, San Diego, CA 92103-8411, USA.
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Palacios R, Santos J, García A, Castells E, González M, Ruiz J, Márquez M. Impact of highly active antiretroviral therapy on blood pressure in HIV-infected patients. A prospective study in a cohort of naive patients. HIV Med 2006; 7:10-5. [PMID: 16313287 DOI: 10.1111/j.1468-1293.2005.00333.x] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To assess the impact of highly active antiretroviral therapy (HAART) on the blood pressure (BP) of naive patients after 1 year of treatment. METHODS A prospective, observational study of 95 HIV-positive patients in our Unit starting HAART between January 2001 and October 2002 and maintaining the same regimen for 48 weeks of follow-up was carried out. Data on blood pressure (BP) and demographic, epidemiological, clinical, immunovirological and therapeutic characteristics related to HIV infection were collected prior to HAART and at week 48. High blood pressure (HBP) [systolic BP (SBP) > or =140 mm Hg and/or diastolic BP (DBP) > or =90 mm Hg] was defined according to international criteria. RESULTS Of the 95 patients, 78 were men, 44% had AIDS and 68% were smokers, and their mean age was 40 years. At week 48 the prevalence of HBP was 26% and SBP, DBP and pulse pressure (PP) increased (121.8 versus 116.6 mm Hg, P=0.0001; 76.3 versus 69.7 mm Hg, P=0.004; 46.9 versus 43.8 mm Hg, P=0.001, respectively). Univariate analysis showed that HBP was associated with older age, higher body mass index (BMI), higher baseline lipids, and higher baseline BP. A linear regression model adjusting for age and sex suggested a significant impact of older age, higher baseline SBP, higher baseline hypercholesterolaemia and lower baseline CD4-cell count on SBP increase. CONCLUSIONS Blood pressure increased after 48 weeks of HAART, leading to an important prevalence of hypertension. The increase in SBP depended on age and baseline lipid profile and immunological status. BP should be periodically measured and treated when necessary in HIV-infected patients on HAART.
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Affiliation(s)
- R Palacios
- Infectious Diseases Unit, Internal Medicine Department, Virgen de la Victoria Hospital, Malaga, Spain.
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Zhou H, Pandak WM, Hylemon PB. Cellular mechanisms of lipodystrophy induction by HIV protease inhibitors. ACTA ACUST UNITED AC 2006. [DOI: 10.2217/17460875.1.2.163] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Bongiovanni M, Bini T, Cicconi P, Landonio S, Meraviglia P, Testa L, Di Biagio A, Chiesa E, Tordato F, Biasi P, Adorni F, Monforte AD. Predictive factors of hyperlipidemia in HIV-infected subjects receiving lopinavir/ritonavir. AIDS Res Hum Retroviruses 2006; 22:132-8. [PMID: 16478394 DOI: 10.1089/aid.2006.22.132] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
We studied 382 multiexperienced HIV-infected patients followed up for > or =3 months after starting lopinavir/ritonavir (LPV/r) to identify the factors predicting hypertriglyceridemia and high non-HDL cholesterol levels (triglycerides > or =200 mg/dl and/or non-HDL cholesterol > or =190 mg/dl) after 6 and 12 months of LPV/r exposure. The predictors of hypertriglyceridemia were higher baseline triglyceride levels [OR: 2.28 (95% CI: 1.67-3.12) for each additional 100 mg/dl; p = 0.001], the total duration of antiretroviral treatment [OR: 1.26 (95% CI: 1.12-1.41) for each additional year; p = 0.01], CDC stage C (OR: 2.06; 95% CI: 1.24-3.88; p = 0.02), and male gender (OR: 2.52; 95% CI: 1.42-4.74; p = 0.02); intravenous drug abusers seem less likely to develop the event (OR: 0.52; 95% CI: 0.37-0.92; p = 0.03). The predictors of high non-HDL cholesterol levels were higher baseline levels [OR: 3.92 (95% CI: 1.92-6.24) for each additional 100 mg/dl; p = 0.001) and the combination of NRTIs and NNRTIs with LPV/r (OR: 1.83; 95% CI: 1.10-3.69; p = 0.03). The 75 patients stopping LPV/r showed a significant reduction in median triglyceride and non-HDL cholesterol levels after 3 months of 39 mg/dl and 20 mg/dl (p = 0.01 for both), respectively. Patients with high triglyceride and non- HDL cholesterol levels at the start of LPV/r treatment are at higher risk of developing hyperlipidemia.
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Affiliation(s)
- Marco Bongiovanni
- Institute of Infectious Diseases and Tropical Medicine, Luigi Sacco Hospital, University of Milan, via G.B. Grassi 74, 20157 Milan, Italy.
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Zhou H, Pandak WM, Lyall V, Natarajan R, Hylemon PB. HIV protease inhibitors activate the unfolded protein response in macrophages: implication for atherosclerosis and cardiovascular disease. Mol Pharmacol 2005; 68:690-700. [PMID: 15976036 DOI: 10.1124/mol.105.012898] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Human immunodeficiency virus (HIV) protease inhibitors have been successfully used in highly active antiretroviral therapy for HIV-1 infection. Treatment of patients infected with HIV with HIV protease inhibitors is unfortunately associated with a number of clinically significant metabolic abnormalities and an increased risk of premature atherosclerosis and myocardial infarction. However, the cellular/molecular mechanisms of the HIV protease inhibitor-induced lipid dysregulation and atherosclerosis remain elusive. Macrophages are the most prominent cell type present in atherosclerotic lesions and play essential roles in both early lesion development and late lesion complications. In this study, we demonstrate that three different HIV protease inhibitors (ritonavir, indinavir, and atazanavir) induce endoplasmic reticulum stress and activate the unfolded protein response in mouse macrophages. Furthermore, at therapeutic concentrations (5-15 microM), these HIV protease inhibitors were found to increase the levels of transcriptionally active sterol regulatory element binding proteins, decrease endogenous cholesterol esterification, cause the accumulation of free cholesterol in intracellular membranes, deplete endoplasmic reticulum calcium stores, activate caspase-12, and increase apoptosis in macrophages. These findings provide possible cellular mechanisms by which HIV protease inhibitors promote atherosclerosis and cardiovascular disease in HIV-1 infected patients treated with HIV protease inhibitors.
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Affiliation(s)
- Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, P.O. Box 980678, Richmond, VA 23298-0678, USA
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Abstract
There is no doubt that highly active antiretroviral therapy (HAART) has been the most important progress in the therapy of human immunodeficiency virus (HIV)-infected patients in the last decade. A growing number of observations suggest that the beneficial effects of HAART also include improvement of HIV-related renal complications. Consequently, the cohort of HIV-infected patients requiring HAART has increased and includes patients with preexisting nephropathies, whether related or unrelated to HIV infection. However, some antiretroviral drugs may have renal- and life-threatening side-effects, especially if underlying renal abnormalities exist. In this review, we focus on those aspects that require particular attention in preventing new health complications in HIV-infected patients.
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Affiliation(s)
- Eric Daugas
- Service de Nephrologie B, Hôpital Tenon, AP-HP, Paris, France.
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Latham V, Stebbing J, Mandalia S, Michailidis C, Davies E, Bower M, Gazzard B, Nelson M. Adherence to trizivir and tenofovir as a simplified salvage regimen is associated with suppression of viraemia and a decreased cholesterol. J Antimicrob Chemother 2005; 56:186-9. [PMID: 15911551 DOI: 10.1093/jac/dki170] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Treatment failure during highly active antiretroviral therapy (HAART) is ultimately common and associated with the development of resistance mutations. Trizivir (zidovudine/lamivudine/abacavir) and tenofovir disoproxil fumarate may improve adherence and enhance virological suppression in individuals who have failed previous regimens. METHODS Individuals were identified who had failed previous HAART and who were then prescribed trizivir and tenofovir. Viral load and genotypic information were obtained to assess virological response. RESULTS One hundred and twenty-two individuals were identified from a database containing 5883 patients. In a last observation carried forward intention to treat analysis, 34% of individuals achieved an undetectable viral load of <50 copies/mL at 1 year. Of those who were able to remain on treatment for 1 year, 65% achieved undetectability. We observed no effect regarding previous regimens on viral outcome. Accumulation of TAMs (thymidine analogue mutations) was associated with a decrease in the number of patients achieving an undetectable viral load (with <2 TAMs present 38% of patients developed undetectable viral loads, > or =1;2 TAMs 17% undetectable; P = 0.03). Using the mean cell volume as a measure of compliance, those with higher values were more likely to achieve a viral load <50 copies/mL (P = 0.04). A beneficial effect on cholesterol was noted regardless of virological outcome. CONCLUSIONS In compliant heavily pre-treated individuals with less than 2 TAMs, salvage therapy with trizivir and tenofovir is associated with suppression of viraemia and an improved lipid profile.
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Affiliation(s)
- Victoria Latham
- The St Stephen's Centre, The Chelsea and Westminster Hospital, London, UK
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Kulkarni R, Soucie JM, Evatt BL. Prevalence and risk factors for heart disease among males with hemophilia. Am J Hematol 2005; 79:36-42. [PMID: 15849761 DOI: 10.1002/ajh.20339] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
There have been conflicting reports in the literature about the protective effect of hemophilia on the occurrence of ischemic heart disease (IHD). Circulatory disease has been reported as the second most common cause of death in persons with hemophilia in the United States. In addition to diabetes and hypertension, high levels of FVIII, as may occur during factor concentrate infusions, may increase IHD risk in this population. To estimate the prevalence of heart disease and examine factors associated with IHD and other heart diseases among persons with hemophilia, we analyzed data collected from the medical records of 3,422 males with hemophilia living in six U.S. states from 1993 to 1998. Heart disease cases were ascertained from among 2,075 persons who were hospitalized at least once during the 6-year period. Of these, 48 were diagnosed with IHD and 106, with other types of heart disease. The age-specific prevalence of IHD ranged from 0.05% in those under 30 years to 15.2% in those 60 years or older. Hospital discharge rates in males with hemophilia with IHD and other types of heart disease were lower compared to rates in age-matched U.S. males. In our cohort, as in the general population, IHD was independently associated with age, hypertension, diabetes, and hyperlipidemia. Other heart diseases were associated with HIV infection, hypertension, hemophilia B, and diabetes. In summary, persons with hemophilia have unique risk factors such as infusion of factor concentrates and infection with HIV that may predispose them to heart disease as their life expectancy increases.
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Affiliation(s)
- Roshni Kulkarni
- Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan, USA
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Zimmet P. Epidemiology of diabetes mellitus and associated cardiovascular risk factors: focus on human immunodeficiency virus and psychiatric disorders. Am J Med 2005; 118 Suppl 2:3S-8S. [PMID: 15903289 DOI: 10.1016/j.amjmed.2005.01.044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Type 2 diabetes mellitus and obesity have reached epidemic proportions in many developing and developed nations, leading to talk of the "twin epidemics." The latest projections from the International Diabetes Federation suggest that 190 million people worldwide currently have type 2 diabetes. In addition, > or = 300 million people worldwide have impaired glucose tolerance (IGT). These statistics represent an epidemic of major proportions--possibly the largest epidemic in human history--in terms of glucose intolerance and cardiovascular disease (CVD) risk because individuals with IGT are at substantially higher risk for diabetes and CVD than are members of the general population. Along with IGT, the metabolic syndrome comprises other major CVD risk factors, including insulin resistance, central obesity, and dyslipidemia; insulin resistance has been implicated as the single most common cause of the syndrome. Although the exact prevalence of the metabolic syndrome is unknown, the syndrome is widespread among adults in developed nations, becoming more prevalent with age. Epidemiologic data suggest that in patients with schizophrenia or affective disorders, both diabetes and obesity are 1.5 to 2.0 times more prevalent than in the general population. Furthermore, because adverse effects of certain therapies for human immunodeficiency virus (HIV) infection and psychiatric disorders increase the risk for developing diabetes, obesity, and the metabolic syndrome, such therapies should be carefully chosen, particularly considering CVD risk. Appropriate therapy may be determined via screening of patients for levels of fasting blood glucose and lipids, as well as other CVD risk factors, before initiating use of second-generation antipsychotic agents or highly active antiretroviral therapy.
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Affiliation(s)
- Paul Zimmet
- International Diabetes Institute, Caulfield, Victoria, Australia.
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Kovacic JC, Martin A, Carey D, Wand H, Mallon PWG, Feneley MP, Emery S, Cooper DA, Carr A. Influence of Rosiglitazone on Flow-Mediated Dilation and Other Markers of Cardiovascular Risk in HIV-Infected Patients with Lipoatrophy. Antivir Ther 2005. [DOI: 10.1177/135965350501000113] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Antiretroviral therapy for HIV infection is commonly complicated by lipoatrophy, insulin resistance and dyslipidaemia. In HIV-uninfected adults with insulin resistance or type 2 diabetes, thiazolidinediones can lower blood pressure and improve both insulin sensitivity and endothelial function. This study sought to investigate the effects of rosiglitazone on endothelial function and other markers of cardiovascular risk in patients with HIV-related lipoatrophy. Methods HIV-infected, lipoatrophic adults receiving anti-retroviral therapy were randomized to receive either rosiglitazone 4 mg or matched placebo, twice daily. Percentage flow-mediated forearm arterial dilation (FMD%) was measured at weeks 0, 12, 24 and 48, together with other markers of vascular risk (blood pressure, lipids, glycaemic parameters, adiponectin and leptin). Results Out of 64 enrolled adults, 44 (69%) attended all visits (23 rosiglitazone, 21 placebo). Relative to placebo, at week 48, rosiglitazone decreased systolic blood pressure (8 mmHg, P=0.03), insulin (3 μIU/ml, P=0.02), insulin resistance ( P=0.03) and leptin (0.6 ng/ml, P=0.02), whilst adiponectin was increased (3.3 μg/ml, P<0.0001). However, rosiglitazone increased total cholesterol (49.1 mg/dl, P=0.001), low-density lipoprotein cholesterol (23.5 mg/dl, P=0.01) and triglycerides (146 mg/dl, P=0.06). Mean baseline FMD% for the entire cohort was moderately impaired (4.5%). Compared with baseline, mean on-treatment FMD% increased by 0.8% with rosiglitazone and decreased by 0.3% with placebo (mean difference 1.1%, 95% CI -0.2 to 2.5, P=0.09). Conclusions Rosiglitazone has minimal effect on flow-mediated dilation in HIV-infected lipoatrophic adults. However, despite worsening of the lipid profile, the overall effect of rosiglitazone on the cardiovascular risk profile in these subjects was positive.
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Affiliation(s)
- Jason C Kovacic
- Cardiology Department, Immunology and Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, Australia
| | - Allison Martin
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
| | - Dianne Carey
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
| | - Handan Wand
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
| | - Patrick WG Mallon
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
- Department of HIV, Immunology and Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, Australia
| | - Michael P Feneley
- Cardiology Department, Immunology and Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, Australia
| | - Sean Emery
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
| | - David A Cooper
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
- Department of HIV, Immunology and Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, Australia
| | - Andrew Carr
- Department of HIV, Immunology and Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, Australia
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de Gaetano Donati K, Rabagliati R, Iacoviello L, Cauda R. HIV infection, HAART, and endothelial adhesion molecules: current perspectives. THE LANCET. INFECTIOUS DISEASES 2004; 4:213-22. [PMID: 15050939 DOI: 10.1016/s1473-3099(04)00971-5] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In this review we summarise the data on the effects of HIV infection and its therapy with antiretroviral drugs on adhesion molecules, considered to be potential biomarkers of endothelial cell function. This is a recent area of interest, given the unexpected associations between antiretroviral therapy, metabolic alterations of lipid profile, and the risk of cardiovascular disease in the absence of clear pathogenetic links. Although convincing prospective data are still scarce, it seems timely to elucidate the potential value of non-invasive, inexpensive tests for predicting cardiovascular risk in HIV-infected patients undergoing highly active antiretroviral therapy (HAART). Endothelial function, the most plausible link between infection, inflammation, and atherosclerosis, has been investigated since the beginning of the HIV epidemic. Increased concentrations of soluble adhesion molecules, such as those from the selectin and immunoglobulin families, have consistently been reported in HIV-positive patients. The introduction of HAART has renewed interest in the study of endothelial function in HIV-positive patients, in view of some HAART-related metabolic abnormalities (hyperlipidaemia, hyperglycaemia, fat redistribution) and several large reports of premature coronary artery disease. Whether HAART reduces endothelial injury associated with HIV infection or contributes to further endothelial cell activation is still a matter of controversy. Also unclear is whether HAART acts directly or indirectly, and if protease inhibitors and other classes of antiretroviral drugs differ in their proatherosclerotic effects. This article attempts to define the state of these emerging issues, identifies areas of controversy and of potential clinical relevance, and suggests some directions for future research.
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