Bernardino, Jose Ignacio MD*; Mora, Marta MD*; Zamora, Francisco Xavier MD*; Arribas, Blanca RN*; Montes, Maria Luisa MD*; Pascual-Pareja, Francisco MD*; Jose, Belen San BSc†; Peña, Jose Maria MD, PhD*; Arribas, Jose Ramon MD*
Although antiretroviral therapy has reduced overall mortality,1 there is still concern about long-term cardiovascular complications in patients infected with HIV. Recent reports suggest that life expectancy in asymptomatic HIV-infected patients approaches that of age and gender-matched uninfected individuals,2-4 so greater cardiovascular morbidity is expected in this aging population.
At present it is still unclear if chronic HIV infection or antiretroviral treatment play an important role in hypertension (HTN) development. Apart from tobacco use, diabetes, and dyslipidemia, HTN is part of the main modifiable cardiovascular risk factors, but it has not been completely studied in HIV-infected patients. There are conflicting data about the prevalence of HTN in this population, which varies from 5% to 38%.5-8 This large difference in estimation can be related to differences in the diagnostic method (medical history 5,9 or repeated blood pressure (BP) measurements8) and different diagnostic criteria for HTN used. The majority of the data come from historic cohorts with no specific design to study the prevalence of cardiovascular risk factors.10,11 Given these uncertainties, it is still unknown whether HIV-infected patients have a different HTN prevalence compared with the general population. Some studies show a higher prevalence,7 whereas others show the opposite.8,12,13
Although office BP measurements are routinely used to diagnose and guide antihypertensive therapy, it is well known that office BP might inaccurately reflect an individual real BP level. Ambulatory blood pressure monitoring (ABPM) has several advantages over office BP measurements. ABPM values correlate with HTN-related organ damage more closely than office BP values do,14 more accurately predict cardiovascular events,15 and allow circadian pattern and morning BP rise to be studied.
It has been estimated that isolated office hypertension (IOH), formerly called white coat HTN, may be present in 15% of the general population and in one-third in patients in whom HTN is initially suspected.16,17 There are few studies in HIV-infected patients with ABPM to determine the prevalence of IOH. Due to the special characteristics of the HIV clinics, that can increase anxiety levels, we hypothesized than IOH might be more frequent in HIV-infected patients than in the general population. We therefore conducted this study to determine HTN and IOH prevalence in HIV-infected patients on routine clinical care using ABPM procedures.
PATIENT AND METHODS
A cross sectional study of randomly selected patients was conducted at the Hospital La Paz HIV Unit in Madrid. Our clinic is located in a university-based public hospital and provides comprehensive medical care, including a tobacco cessation clinic to HIV-infected adults. During a 6-month period (November 2008 to April 2009), all patients attending regular appointments during a randomly selected weekday (in total 21 different days) were invited to participate. The inclusion criteria were as follows: HIV-infected patients older than 18 years who consented to participate. The exclusion criteria were as follows: pregnancy, chronic use of illicit drugs (cocaine or amphetamines), and use of drugs that potentially can induce HTN (oral contraceptives, steroids, NSAID, tryciclic antidepressant, monoamine oxidase inhibitors). Patients with an arm circumference >42 cm and/or cardiac arrhythmias (eg, atrial fibrillation, ectopic ventricular beats) were excluded due to the impossibility of performing accurate ABPM measurements. The diagnosis of HTN and IOH was made in accordance with the 2007 European Society of Cardiology and European Society of Hypertension guidelines.18
The primary objective was to determine HTN and IOH prevalence, and secondary objectives were to study circadian BP patterns and assess clinical factors associated with HTN.
For all patients, information on prescribed drugs and laboratory parameters was obtained from clinical and laboratory databases. The following variables were specifically recorded: family history of premature cardiovascular disease (male at age <55 years, female at age <65 years), family history of HTN, tobacco use (never, previous smoker, current), and presence of lipoatrophy (yes/no according to HOPS questionnaire).19
Anthropometric measures were also collected as follows: hip, waist and arm circumferences, weight, height, and total body fat (%) by bioelectrical impedanciometry (OMRON BF400).
The study was approved by the Hospital La Paz Institutional Review Board, and written informed consent was obtained from all patients.
All BP measurements were taken in the morning of a working day in the office by a trained practitioner, in accordance with European Society of Cardiology and European Society of Hypertension recommendations.18 After a 5-minute rest in a sitting position, 3 BP readings were taken with 2-minute intervals. BP values were estimated as the mean of the last 2 readings. After 1 minute standing, a single BP reading was recorded. All readings were taken with a validated semiautomatic oscillometric device (Omron HEM 7001-E. Omron Corp, Tokyo, Japan). A suitable cuff was used depending on arm circumference. If clinic BP was 140/90 mm Hg or higher and the patient had not prior diagnosis of HTN, an ABPM procedure was scheduled.
Ambulatory Monitoring Assessment
A 24-hour (morning to morning) ABPM was performed through a validated oscillometric device (Spacelabs 90207) with the BP readings set at 15-minute intervals during daytime (from 07 AM to 10 PM) and 20-minute intervals during night (from 11 PM to 07 AM). Registries were performed on working days, in nondominant arm, and the patients were instructed to maintain their usual activities and keep arm extended and immobile at the time of cuff inflation.
The registry was considered valid if ≥60% of systolic blood pressure (SBP) and diastolic blood pressure (DBP) paired registries were successfully recorded during the day-time and night-time period, and at least 2 BP measurements were available per hour.
Nocturnal decline and circadian patterns were defined by calculating the percentage of reduction in SBP during the night using the following formula: (mean daytime BP − mean nighttime BP)/mean daytime BP.
For the present study we used the following definitions:
* Prior diagnosis of HTN: at the time of inclusion, patient was receiving antihypertensive therapy because of a prior diagnosis of HTN.
* Office HTN: subjects with an office SBP ≥140 mm Hg or DBP ≥90 mm Hg.
* ABPM HTN: subjects with office HTN and an average SBP (ABPM, daytime) ≥135 mm Hg or average DBP (ABPM, daytime) ≥85 mm Hg.
* IOH: subjects with office HTN with a daytime average BP <135 mm Hg systolic and 85 mm Hg diastolic.
* HTN: ABPM HTN or prior diagnosis of HTN.
* Normal dipping pattern (dipper): when the reduction in the average SBP night time was > 10% mean SBP daytime. When this reduction was >20%, the patient was diagnosed as an extreme dipper.
* Abnormal dipping pattern (nondipper): when average night time SBP reduction was <10% with respect to daytime values. When mean SBP night time was higher than mean SBP daytime, the patient was classified as a riser.
To calculate sample size, we assumed a possible prevalence of HTN in the study population of 25%. With this prevalence, 288 patients would be required to achieve a precision of ±5% [95% confidence interval (CI)]. With an anticipated nonacceptance rate of 5% final sample size was 302 patients.
Data are presented as frequencies and percentages for categorical variables and means ± SD for continuous variables. Median values and interquartile range were used if there was a skewed distribution. Groups of patients were compared using the χ2 test for categorical data and parametric or nonparametric tests for continuous variables as needed. Factors associated with HTN were examined by univariate and multivariate logistic regression models. In the forward stepwise regression model, those independent variables in the univariate analysis (P value < 0.05) were included. Gender and body mass index although nonsignificant in the univariate analysis were included because of their clinical relationship with HTN. Metabolic syndrome was not included in the model because HTN is part of its definition.
The SPSS for Windows software package v9.0 (SPSS Inc., North Chicago, IL) was used for statistical analysis.
The study included 310 patients. Of the 310 patients, 20 (6.5%) had a prior diagnosis of HTN, and, as per protocol, ABPM procedure was not performed. Forty-four patients had an office BP measurement ≥140/90 mm Hg and were offered a 24-hour ABPM procedure. Only 1 patient refused (Fig. 1). Patients were mostly male and white, and the duration of HIV infection varied from 1 to 20 years (9.9 ± 7.8). Two hundred and nineteen patients (70.6%) were receiving highly active antiretroviral therapy, and 83 (26.8%) were antiretroviral naive (Table 1).
Prevalence of HTN and IOH
Forty-four of 310 patients had office HTN for a prevalence of 14.2% (95% CI: 10.3 to 18.1%). If we add the 20 patients with a “prior diagnosis of HTN,” the frequency of office HTN and a prior HTN diagnose was 20.6% (95% CI: 16.1 to 25.2). Prevalence of other categories of HTN are shown in Table 2.
Clinical Characteristics Associated With HTN
For this analysis, we grouped patients without HTN and patients with only IOH (n =17). In the bivariate analysis, comparing patients with HTN (Prior diagnosis and ABPM HTN) and without HTN (normotensive and IOH), a number of significant differences were found. Hypertensive patients were older (48 vs. 41 years; P < 0.001), with a longer duration of HIV infection (13 vs. 9.3 years; P = 0.001) and a lower CD4 count nadir (149 vs. 203 cells per cubic millimeter; P = 0.023). Patients with HTN more frequently had lipoatrophy (45.7% vs. 25.7%; P = 0.008) and were more likely to receive antiretroviral therapy (87% vs. 68%; P = 0.008) than normotensive patients. The clinical characteristics by groups are shown in Table 3. Globally, HIV-infected patients with HTN had more cardiovascular risk factors than the normotensive ones.
Multivariate analysis identified 3 independent factors associated with HTN presence and 1 protective factor. Each year of age raised risk by 8% (OR: 1.08, 95% CI: 1.03 to 1.12; P < 0.001). Family history of HTN (OR: 2.24, 95% CI: 1.09 to 4.59; P = 0.027) and number of antiretroviral regimens (OR: 1.2, 95% CI: 1.07 to 1.34; P = 0.001) also increased the risk for HTN, whereas female gender lowered the risk (OR: 0.27, 95% CI: 0.09 to 0.81; P = 0.02) (Table 4).
When we performed the same analysis, excluding IOH patients, the same results were found (data not shown).
Twenty-six of 43 HIV-infected patients (60%) who undergone an ABPM procedure had an abnormal dipping pattern. Extreme dippers accounted for 5% (n = 2) and risers for 12% (n = 5). There were no specific differences in clinical characteristics according to dipping status except for higher CD4 count in nondipping pattern (612 vs. 425 cells/mm3; P = 0.017).
Our study has found a prevalence of HTN of 14.8% in HIV-infected patients. A major strength of our study is the strict methodology used for BP measurement and the use of ABPM for diagnosis of HTN. Although ABPM is not mandatory for HTN diagnosis, this method is considered the gold standard.20 Three studies have employed ABPM in HIV-infected patients to evaluate dipping patterns in patients already diagnosed with HTN,21 to identify factors associated with BP measured by ABPM,22 and to evaluate circadian BP patterns in normotensive HIV-infected patients.23 However, to the best of our knowledge, ours is the first study that has used ABPM for HTN diagnosis in HIV-infected patients.
One of the advantages of the ABPM procedure is its capability for diagnosing IOH. In our study, IOH prevalence in patients with office HTN and no prior diagnosis of HTN was 39.5% (95% CI: 25 to 54). This prevalence is slightly higher than the 1 reported in the general population (20% to 29%),16,17,24 and in untreated, hypertensive, HIV-infected patients (26%),22 It should be noted that if we assume that 39.5% of the 20 patients with a prior diagnosis of HTN could had in reality IOH, then a more accurate prevalence of HTN would be 12.3%.
Although IOH has been associated with less cardiovascular morbidity than sustained HTN,17,25 its recognition is important because IOH is a predictor of future sustained HTN and target organ damage. In a recent report from the PAMELA study, patients with IOH had a 2.5 times higher risk of becoming sustained hypertensive.26 Other reports have demonstrated an association between IOH and target organ damage such as intima media thickness or left ventricular mass,25,27,28 although this is not consistently observed.29
In studies where a relationship between HTN and HIV infection has been evaluated, risk factors for HTN were mainly classic cardiovascular risk factors, increasing age and obesity, and not the use of highly active antiretroviral therapy.12,30 In addition, lipoatrophy and lipohypertrophy have been associated with HTN.31 In one study, patients with lipoatrophy had a 4-fold risk of HTN compared with patients without morphologic changes. The association of lipohypertrophy with HTN seems to be mediated by an increase in body mass index.31
In our study, multivariate analysis showed that age, family history of HTN, and number of antiretroviral regimens were associated with a recent diagnose of HTN. Female sex had a protective effect. Other metabolic factors such as abdominal circumference and lipoatrophy were associated with HTN only in the univariate analysis.
The number of antiretroviral regimens received could be an indirect measurement of ART duration and cumulative drug-related toxicity. One study comparing hypertensive HIV-infected patients receiving ART with the general population, showed a significant relation between HTN and duration of HIV treatment. This study is the only one, which includes general population controls.8 The lack of an association of HTN with lipoatrophy in our multivariate analysis could be due to our definition of lipoatrophy (dichotomous variable instead of a quantitative variable) and because this morphologic abnormality was also related to cumulative drug toxicity.
Although our study was not designed for this purpose, we observed that a nondipping pattern was present in 60% of patients with office HTN. Recent articles have shown that nondipping patterns are more common in HIV-infected hypertensive patients than in non-HIV-infected hypertensive patients.21,23
The high frequency of nondipping pattern found our study is somewhat surprising, taking into account that prevalence of nondipping pattern in a large study in HIV-negative hypertensive patients was 39%.32 Nondipping pattern frequencies of around 60% have been reported in high cardiovascular-risk hypertensive patients,33 but this is not the case in our HIV-infected patients who have a recent diagnosis of HTN. The high prevalence of a nondipping pattern found in our study could have been caused by a different life style in our HIV-infected patients with different sleep period times from general population.
Our study is limited by a relatively small sample size and by having performed BP measurements on a single day instead of repeated measurements days or weeks apart as state by European Guidelines.18 This could result in an overestimation of IOH. In addition, several variables such as lipoatrophy, that had been previously associated with HTN, were not precisely recorded. In our study, lipoatrophy was clinically defined instead of using a more accurate imaging test. We have used number of antiretroviral regimens as an indirect measure of treatment duration.
In summary, our study shows that using ABPM, HTN prevalence in HIV-infected patients is lower than previously reported. Because IOH occurs in 39% of HIV-infected patients with presumed HTN, noninvasive BP monitoring could be useful to confirm HTN diagnosis and help take better decisions regarding treatment in hypertensive subjects. Although HIV duration was not associated with HTN in this study, total exposure to antiretroviral can be a risk factor for HTN in HIV-infected patients.
We thank all the patients and especially the nurses involved in the study (Marta Galvez and Juan Miguel Castro). We also thank Mr Martin J. Smyth, BA, for his help in correcting the English.
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