Combination antiretroviral therapy (CART) has resulted

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1 AJH 2005; 18: Hypertension in HIV-Infected Patients: Prevalence and Related Factors Carlos Jericó, Hernando Knobel, Milagro Montero, María L. Sorli, Ana Guelar, Juan L. Gimeno, Pere Saballs, Jose L. López-Colomés, and Juan Pedro-Botet Background: Little is known about hypertension in the HIV-infected population. This study aimed to assess the prevalence of hypertension and related factors in HIVinfected patients. Methods: In this prospective cross-sectional study, 710 HIV-infected patients (626 on combination antiretroviral therapy and 84 naive) managed at the outpatient clinic of a tertiary hospital during 2003 and 802 controls completed the study protocol consisting of medical examination and a 6-month follow-up period including three control visits. Results: Hypertension prevalence was 13.1% in HIVinfected patients and 13.5% in the control group. Age (per 10-year increment) (odds ratio [OR]: 1.92; 95% confidence interval [CI]: ), body mass index (OR: 1.18; 95% CI: ), and lipoaccumulation pattern of fat redistribution (OR: 2.26; 95% CI: ) were independently and significantly associated with the presence of hypertension in HIV-infected patients at logistic regression analysis. Conclusions: The present results suggest no meaningful difference in prevalence of hypertension between subjects with and without HIV infection. Thus, the influence of combination antiretroviral therapy appears to have little impact on the prevalence of hypertension. Am J Hypertens 2005;18: American Journal of Hypertension, Ltd. Key Words: Antiretroviral therapy, HIV, hypertension, protease inhibitors. Combination antiretroviral therapy (CART) has resulted in durable suppression of HIV replication, prevention of AIDS-defining opportunistic infections and malignancies, and a substantial impact on survival rate and quality of life in HIV-infected patients. 1 However, the potential for maintaining these patients on treatment for decades may be limited by a variety of metabolic abnormalities observed in patients on CART, including dyslipidemia, fat redistribution, and insulin resistance, 2,3 particularly when therapy contains protease inhibitors. 4 This fact has raised the concern that the HIVinfected population may be at increased risk for cardiovascular disease in the long term, as has been described in two large prospective studies. 5,6 The absolute cardiovascular risk in any individual is determined by a complex interplay of several risk factors that include older age, positive family history, smoking, hypertension, elevated blood lipids, and diabetes. 7 In the pre-cart era, elevated blood pressure (BP) was frequently associated with HIV-related complications such as renal failure and vasculopathy. 8 Recent reports raise the suspicion that CART may also induce hypertension A few comparative studies on BP in HIV-infected patients, mainly those with lipodystrophy or the metabolic syndrome, have been reported. 10,12,15 Because the identification and management of cardiovascular risk factors in HIV-infected patients has become a more pressing issue, hypertension must be taken into account in this population. The present study focuses on the prevalence of hypertension and possible related factors in a large group of HIVinfected patients. Methods Study Population A cross-sectional study was conducted in HIV-infected patients managed at the outpatient Infectious Disease Unit of the Hospital del Mar, Barcelona, from January through December 2003 and followed for at least 6 months to complete three visits. A control group to compare hypertension prevalence was recruited at the same time from hospital and university staff, nonretributed blood donors, Received January 28, First decision May 10, Accepted May 10, From the Department of Medicine, Hospital del Mar. Universidad Autónoma de Barcelona, Barcelona, Spain. Dr. C. Jericó is the recipient of a grant from the Fundación IMIM (Institut Municipal d Investigació Mèdica). Address correspondence and reprint requests to Prof. J. Pedro-Botet, Department of Medicine, Passeig Marítim, 25-29, Barcelona. Spain; @imas.imim.es /05/$ by the American Journal of Hypertension, Ltd. Downloaded from doi: /j.amjhyper Published by Elsevier Inc.

2 AJH November 2005 VOL. 18, NO. 11 HYPERTENSION IN HIV-INFECTED PATIENTS 1397 and subjects who attended the ophthalmology outpatient clinic for visual acuity examination. The protocol study approved by the local Ethics Committee consisted of physical examination. All participants were 20 years of age or older and were evaluated by trained physicians after giving their informed consent. Exclusion criteria for patients included withdrawal of CART and evidence of clinical signs of active AIDS in the 3 months before entry and during the study owing to their possible impact on anthropometric parameters and BP values. Data Collection Age, gender, HIV disease stage according to the 1993 Centers for Disease Control and Prevention (CDC) classification of HIV disease, 16 HIV exposure (mutually exclusive in the following order: intravenous drug use, male homosexual activity, heterosexual activity), and type and duration of CART were recorded. Lipodystrophy was defined and categorized by the blinded physician (HK)- assessed presence of peripheral lipoatrophy (face, arms, legs, buttocks, and prominent veins), central lipohypertrophy (abdomen, breasts, dorsocervical region), and mixed lipodystrophy. Weight and height were measured by standard methods. After the participant had rested seated for 10 min in a quiet room, BP was measured in the left arm with the elbow flexed at heart level by the same physician (CJ) using a 1042 Riester sphygmomanometer (Jungingen, Germany), with diastolic pressures at Korotkoff phase 5 (disappearance of sounds). Three readings were obtained, and the average of the second and third systolic and diastolic BP readings was used in the analyses. Patients and controls were seen at least three times during the 6-month follow-up period. Hypertension diagnosis was defined when the two readings obtained at the three consecutive visits were 140 or 90 mm Hg, or current use of antihypertensive therapy. Pulse pressure was calculated as systolic minus diastolic BP. Creatinine clearance was estimated by the method of Cockcroft and Gault. 17 Statistical Analysis Student t test was performed to assess differences between the two means. When data were not normally distributed, Mann-Whitney U test was used. Either 2 test or Fisher s exact test was used to test the degree of association of categorical variables. Computed factors in the univariate analysis were age, gender, body mass index, HIV transmission group (dichotomized as intravenous drug users versus sexual transmission), HIV clinical stage (dichotomized as asymptomatic, A stage of CDC versus symptomatic, B and C stage of CDC), current and nadir CD4 cell count, plasma HIV RNA categorized as detectable ( 500 copies/ml) or undetectable, lipodystrophy, duration of CART, and type of CART classified as antiretroviral naive, no protease inhibitor exposure, and past or current protease inhibitor exposure. Variables demonstrating a univariate relationship (P.05) with the outcome variable were included in the model to assess the effect of independent variables on hypertension diagnosis. A P value.05 was considered statistically significant. Goodness-of-fit was verified with the Hosmer and Lemeshow statistic method. All statistical analyses of database results were performed with the Statistical Package for the Social Sciences (SPSS for Windows, v.11.5, Chicago, IL). Results Of the 805 eligible HIV-infected patients, only 710 (88.2%) agreed to participate in the study protocol and completed all visits. Of these, 626 (88.2%) were on CART and 84 (11.8%) naive. Demographic and clinical characteristics of HIV infection are shown in Table 1. Hypertension was detected in 93 (13.1%) (25 receiving antihypertensive therapy). Eightyeight were on CART and five were naive HIV-infected patients. Among the 802 recruited controls, hypertension was detected in 108 (71 on medication) subjects (13.5%) (Table 1). By gender, the prevalence of hypertension in HIV-infected patients was 15.5% in men and 7% in women and 14.6% and 8.8%, respectively, in the control group. As shown in Table 2, hypertensive HIV-infected patients presented with older age, male predominance, higher body mass index, and pulse pressure compared with normotensive HIV-infected patients. Among the characteristics of HIV disease only the transmission group category significantly differed between hypertensive and normotensive HIV-infected patients. Lipodystrophy was more common among hypertensive patients compared with normotensives (53.8% v 34.0%, P.0001). Moreover, CART, particularly protease inhibitor exposure, was significantly associated with hypertension. Table 3 depicts the multivariate logistic regression analysis and, besides age and body mass index, lipoaccumulation type emerged as significantly and independently associated with hypertension (odds ratio [OR]: 2.26, 95% confidence interval [CI]: ). When lipodystrophy was removed from this model, exposure to protease inhibitors appeared as independently associated with hypertension (OR: 3.37, 95% CI: ; P.027). Discussion Blood pressure is considered an important modifiable risk factor in both primary and secondary cardiovascular prevention, and this is reflected in current clinical statements for the general population, 7 as well as in HIV-infected subjects. 18 Using Joint National Committee-Sixth Report (JNC-VI) criteria, % of HIV-infected patients and 13.5% of the control group were estimated to have hypertension. This estimate is globally lower than that reported in epidemiologic studies for the general population in European countries. 20 However, when comparing the age-

3 1398 HYPERTENSION IN HIV-INFECTED PATIENTS AJH November 2005 VOL. 18, NO. 11 Table 1. Demographic, anthropometric, and HIV infection characteristics of the 710 patients and 802 controls Characteristics Patients Controls P Age (yr, mean SD) Gender (M/F) 511/ /249.2 Body mass index (kg/m 2 ) Current smokers (%) 479 (69.5) 245 (30.5).001 Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse pressure (mm Hg) Subjects with hypertension (%) 93 (13.1) 108 (13.5) NS Hypertensive subjects on antihypertensive therapy (%)* 25 (26.9) 71 (65.7).000 Transmission groups Intravenous drug users (%) 293 (41.3) Homosexuals (%) 240 (33.8) Heterosexuals (%) 158 (22.3) Others and unknown (%) 19 (2.7) Known duration of HIV infection [months (IQR)] 109 (69 153) CD4 nadir cell count [ 10 6 cells/l (IQR)] 201 (76 329) CD4 cell count [ 10 6 cells/l (IQR)] 481 ( ) Viral load 500 copies/ml (%) 362 (65.3) HIV disease category A (%) 339 (47.8) B (%) 139 (19.5) C (%) 232 (32.7) Median time antiretroviral therapy [months (IQR)] 73 (37 99) Antiretroviral therapy exposure Naive (%) 84 (11.8) Without protease inhibitors (%) 158 (22.3) With protease inhibitors (%) 467 (65.9) Lipodystrophy No fat redistribution (%) 450 (63.4) Lipoatrophy (%) 152 (21.4) Lipohypertrophy (%) 24 (3.4) Mixed lipodystrophy (%) 84 (11.8) IQR median interquartile range; NS not significant. * Number of subjects (%) diagnosed of hypertension by the criterion of antihypertensive therapy use. HIV clinical categories: A (asymptomatic, acute HIV, or persistent generalized lymphadenopathy), B (symptomatic, not categories A or C), and C (AIDS-indicator conditions). 16 specific prevalence of epidemiologic hypertension diagnosis, the prevalence among participants aged 35 through 44 years was nearly similar in the present study to that of the European population. 20 We wish to emphasize that 26.9% of HIV-infected subjects with hypertension were detected by the criterion of antihypertensive drug therapy use versus 65.7% of controls. This could indicate that, if recruitment bias was assumed to be improbable, HIV-infected patients were less likely to be treated for hypertension, as the hypertension prevalence was similiar in both groups. Although BP levels are usually categorized in cardiovascular risk studies in the HIV-infected population, 5,21,22 hypertension prevalence as the main study objective has received little attention and data are controversial or vary widely. Potential explanations for these dissimilar results include differences in study design, methodologic aspects, cut-off values for BP, and differences in the patient populations studied. 10,12,15 Our hypertension prevalence was higher than that reported for HIV-infected men of the Aproco cohort, 23 lower than the Italian cohort, 12 and similar to Norwegian cohort. 15 Some aspects of the present study need to be highlighted. First, concerning BP measurement, and according to the American Heart Association, BP was measured with the patient s elbow flexed at heart level. 24 From a clinical viewpoint, this apparently insignificant fact has important implications. In this regard, Hemingway et al 25 found BP readings to be higher when the arm was parallel to the torso and would decrease by 8.8 to 14.4 mm Hg with the arm raised to a perpendicular position. Second, all HIVinfected patients had at least a 6-month follow-up with three visits to support the diagnosis of hypertension and thus avoid hypertension overdiagnosis. In this respect, the initial diagnosis of hypertension could not be clinically confirmed in 47.5% of patients during follow-up. Third, abnormal fat redistribution was more frequently observed in hypertensive HIV-infected patients and, in regression analysis, the presence of a lipoaccumulation pattern of fat

4 AJH November 2005 VOL. 18, NO. 11 HYPERTENSION IN HIV-INFECTED PATIENTS 1399 Table 2. Association between age, gender, HIV disease characteristics, lipodystrophy, and antiretroviral therapy and hypertension Characteristics Hypertensive Patients n 93 (13.1%) Normotensive Patients n 617 (86.9%) P Age (yr, mean SD) Gender Male (%) 79 (84.9) 432 (70.0).003 Female (%) 14 (15.1) 185 (30.0) Current smokers (%) 45 (48.4) 434 (70.3).0001 Body mass index (kg/m 2, mean SD) Pulse pressure (mm Hg, mean SD) Creatinine clearance (ml/min)* Transmission group Intravenous drug users (%) 19 (20.4) 274 (44.4) Others (%) 74 (79.6) 343 (55.6).0001 HIV disease category C (%) 45 (48.4) 261 (42.3) A B (%) 48 (51.6) 356 (57.7).312 Known duration of HIV infection [months (IQR)] 104 (69 159) 111 (71 136).30 CD4 nadir cell count [ 10 6 cells/l (IQR)] 187 (44 314) 204 (80 330).12 CD4 cell count [ 10 6 cells/l (IQR)] 485 ( ) 476 ( ).8 HIV RNA 500 copies/ml No (%) 30 (32.3) 240 (38.8) Yes (%) 63 (67.7) 377 (61.2).2 Lipodystrophy No (%) 43 (46.2) 407 (66.0) Lipoatrophy pattern (%) 24 (25.8) 128 (20.9).0001 Lipoaccumulation pattern (%) 26 (28.0) 82 (13.3) Median time CART [months (IQR)] 75 (57 101) 73 (32 99).09 Antiretroviral therapy exposure Naive (%) 5 (5.4) 79 (12.8) Without protease inhibitor (%) 17 (18.3) 141 (22.9).0111 With protease inhibitor (%) 71 (76.3) 396 (64.3) IQR median interquartile range. * by Cockcroft formula. 17 HIV clinical categories: A (asymptomatic, acute HIV, or persistent generalized lymphadenopathy), B (symptomatic, not categories A or C); and C (AIDS-indicator conditions). 16 redistribution, which includes lipohypertrophy plus mixed forms of lipodystrophy, increased the odds ratio of elevated BP twofold. The link between lipodystrophy and hypertension is not surprising because fat redistribution, hyperlipidemia, insulin resistance, and hyperglycemia have been extensively reported in HIV-infected subjects Table 3. Odds ratio and 95% confidence intervals for hypertension from multivariate analysis of logistic regression analysis for selected variables Variable Adjusted OR 95% CI P Age (per 10-yr increment) Gender Current smokers Body mass index Transmission group Lipoatrophy Lipoaccumulation pattern* Exposure to protease inhibitors CART without protease inhibitor exposure OR odds ratio; CI confidence interval; CART combination antiretroviral therapy. The goodness-of-fit was verified with the Hosmer and Lemeshow statistical method (P.5). * Lipoaccumulation pattern includes lipohypertrophy plus mixed forms.

5 1400 HYPERTENSION IN HIV-INFECTED PATIENTS AJH November 2005 VOL. 18, NO. 11 treated with protease inhibitors. 3,26 Although protease inhibitor therapy was not an independent factor in the logistic regression model, when lipodystrophy was not taken into account in this model, exposure to protease inhibitors emerged as significantly and independently associated with hypertension. Thus, the influence of protease inhibitor therapy on BP levels could, at least in part, be mediated through the development of lipodystrophy. Limitations of the present study are mainly related to the observational design and cross-sectional nature of the current analyses. The results reported herein are only associations from which no conclusions regarding causality can be drawn. Although sociodemographic characteristics of the clinical population studied, such as the high prevalence of current smokers, intravenous drug users, and male predominance, are quite similar to those of the Spanish HIV population in accordance with the National AIDS Registry, 27 data on prevalence results could be generalized with caution to the global HIV population. On the other hand, information on other environmental factors such as physical activity or diet and salt intake was not collected. The present results suggest no meaningful difference in prevalence of hypertension between subjects with and without HIV infection. Considering that the substantial benefits of CART clearly outweigh the possible complications associated with this therapy, we conclude that the influence of CART appears to have little impact on the prevalence of hypertension. However, it must be borne in mind that with progressive aging of the HIV-infected population and the expected long-term use of CART, the need will arise to prevent an increased incidence in elevated BP in this population, particularly those with lipoaccumulation. Acknowledgment We thank Christine O Hara for review of the English version of the manuscript. References 1. Carr A: Improving the study, analysis, and reporting of adverse events associated with antiretroviral therapy. Lancet 2002;360: Hadigan C, Meigs JB, Corcoran C, Rietschel P, Piecuch S, Basgoz N, Davis B, Sax P, Stanley T, Wilson PW, D Agostino RB, Grinspoon S: Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001;32: Carr A: HIV lipodystrophy: risk factors, pathogenesis, diagnosis and management. AIDS 2003;17(Suppl 1): Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, Cooper DA: A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998;12: Mary-Krause M, Cotte L, Simon A, Partisani M, Costagliola D, and the Clinical Epidemiology Group from the French Hospital Database: Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS 2003;17: The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group: Combination antiretroviral therapy and risk of myocardial infarction. N Engl J Med 2003;349: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285: Aoun S, Ramos E: Hypertension in the HIV-infected patient. Curr Hypertens Rep 2000;2: Cattelan AM, Trevenzoli M, Sasset L, Rinaldi L, Balasso V, Cadrobbi P: Indinavir and systemic hypertension. AIDS 2001;15: Sattler FR, Qian D, Louie S, Johnson D, Briggs W, DeQuattro V, Dube MP: Elevated blood pressure in subjects with lipodystrophy. AIDS 2001;15: Galindo Puerto MJ: AHT and HIV a new problem? Nutr Metab Disord HIV Infect 2002;1: Gazzaruso C, Bruno R, Garzaniti A, Giordanetti S, Fratino P, Sacchi P, Filice G: Hypertension among HIV patients: prevalence and relationships to insulin resistance and metabolic syndrome. J Hypertens 2003;21: Chow DC, Souza SA, Chen R, Richmond-Crum SM, Grandinetti A, Shikuma C: Elevated blood pressure in HIV-infected individuals receiving highly active antiretroviral therapy. HIV Clin Trials 2003; 4: Palacios R, Santos J, Castells E, Ruiz J, González M, Márquez M: Blood pressure increases in a cohort of naïve HIV patients starting HAART. XV International AIDS Conference 2004, Bangkok. 15. Bergersen BM, Sandvik L, Dunlop O, Birkeland K, Bruun JN: Prevalence of hypertension in HIV-positive patients on highly active retroviral therapy (HAART) compared with HAART-naive and HIV-negative controls: results from a Norwegian study of 721 patients. Eur J Clin Microbiol Infect Dis 2003;22: Centers for Disease Control and Prevention: 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992; 41: Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1976;16: Dube MP, Stein JH, Aberg JA, Fichtenbaum CJ, Gerber JG, Tashima KT, Henry WK, Currier JS, Sprecher D, Glesby MJ; Adult AIDS Clinical Trials Group Cardiovascular Subcommittee; HIV Medical Association of the Infectious Disease Society of America: Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003;37: Joint National Committee: The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157: Wolf-Maier K, Cooper RS, Banegas JR, Giampaoli S, Hense HW, Joffres M, Kastarinen M, Poulter N, Primatesta P, Rodriguez-Artalejo F, Stegmayr B, Thamm M, Tuomilehto J, Vanuzzo D, Vescio F: Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA 2003;289: Friis-Moller N, Weber R, Reiss P, Thiebaut R, Kirk O, d Arminio Monforte A, Pradier C, Morfeldt L, Mateu S, Law M, El-Sadr W, De Wit S, Sabin CA, Phillips AN, Lundgren JD, for the DAD study group: Cardiovascular disease risk factors in HIV patients association with antiretroviral therapy. Results from the DAD study. AIDS 2003;17:

6 AJH November 2005 VOL. 18, NO. 11 HYPERTENSION IN HIV-INFECTED PATIENTS Hadigan C, Meigs JB, Wilson PWF, D Agostino RB, Davis B, Basgoz N, Sax PE, Grinspoon S: Prediction of coronary heart disease risk in HIV-infected patients with fat redistribution. Clin Infect Dis 2003;36: Saves M, Chene G, Ducimetiere P, Leport C, Le Moal G, Amouyel P, Arveiler D, Ruidavets JB, Reynes J, Bingham A, Raffi F, for the French WHO MONICA Project and the APROCO (ANRS EP11) Study Group: Risk factors for coronary heart disease in patients treated for human immunodeficiency virus infection compared with the general population. Clin Infect Dis 2003;37: Frohlich ED, Grim C, Labarthe DR, Maxwell MH, Perloff D, Weidman WH: Recommendations for human blood pressure determinations by sphygmomanometers: report of a special task force appointed by the Steering Committee, American Heart Association. Circulation 1988;77:501A 514A. 25. Hemingway TJ, Guss DA, Abdelnur D: Arm position and blood pressure measurement. Ann Intern Med 2004;140: Tsiodras S, Mantzoros C, Hammer S, Samore M: Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med 2000;160: Centro Nacional de Epidemiología ISC III: Vigilancia epidemiológica del Sida en España. Situación a 30 de junio de Bol Epidemiol Semanal 2004;12: