JAIDS Journal of Acquired Immune Deficiency Syndromes:
Risk of Cardiovascular Events and Blood Pressure Control in Hypertensive HIV-Infected Patients: Swiss HIV Cohort Study (SHCS)
Nüesch, Reto MD*; Wang, Qing PhD†; Elzi, Luigia MD‡; Bernasconi, Enos MD, MSc§; Weber, Rainer MD‖; Cavassini, Matthias MD¶; Vernazza, Pietro MD#; Thurnheer, Maria C. MD**; Calmy, Alexandra MD, PhD††; Battegay, Manuel MD‡; Bucher, Heiner C. MD, MPH†,‡; for the Swiss HIV Cohort Study
*Division of Infectious Diseases, Hirslanden Klinik St. Anna, Lucerne, Switzerland;
†Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland;
‡Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland;
§Division of Infectious Diseases, Regional Hospital of Lugano, Lugano, Switzerland;
‖Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland;
¶Division of Infectious Diseases, University Hospital Lausanne, Lausanne, Switzerland;
#Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital of St. Gallen, St. Gallen, Switzerland;
**Division of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland; and
††Division of Infectious Diseases, University Hospital of Geneva, Geneva, Switzerland.
Correspondence to: Heiner C. Bucher, MD, MPH, Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Hebelstrasse 10, CH-4031 Basel, Switzerland (e-mail: Heiner.Bucher@usb.ch).
R. Nüesch has received travel grants, honoraria, and unrestricted research grants from Abbott, Bristol-Myers-Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Janssen-Cilag, and Pfizer. H. C. Bucher and Q. Wang are funded by unrestricted grants by santésuisse and the Gottfried and Julia Bangerter-Rhyner-Foundation. H. C. Bucher has received travel grants, honoraria, and unrestricted research grants from Abbott, Bristol-Myers-Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Janssen-Cilag, Pfizer, and ViiV Healthcare. M. Battegay has received unrestricted research or educational grants from Abbott, Bristol-Myers-Squibb, Gilead Sciences, Merck Sharp & Dohme-Chibret, Janssen-Cilag, Pfizer, and ViiV Healthcare. He has served on advisory boards of Abbott, Boehringer-Ingelheim, Gilead Sciences, Janssen-Cilag, Pfizer, and ViiV Healthcare. A. Calmy has received educational grants from Abbott, Gilead Sciences, and Janssen-Cilag and travel grants from Janssen-Cillag.
Supported by the framework of the Swiss HIV Cohort Study and the Swiss National Science Foundation (grant # 33CS30_134277).
Received August 20, 2012
Accepted December 21, 2012
Background: Prevalence of hypertension in HIV infection is high, and information on blood pressure control in HIV-infected individuals is insufficient. We modeled blood pressure over time and the risk of cardiovascular events in hypertensive HIV-infected individuals.
Methods: All patients from the Swiss HIV Cohort Study with confirmed hypertension (systolic or diastolic blood pressure above 139 or 89 mm Hg on 2 consecutive visits and presence of at least 1 additional cardiovascular risk factor) between April 1, 2000 and March 31, 2011 were included. Patients with previous cardiovascular events, already on antihypertensive drugs, and pregnant women were excluded. Change in blood pressure over time was modeled using linear mixed models with repeated measurement.
Results: Hypertension was diagnosed in 2595 of 10,361 eligible patients. Of those, 869 initiated antihypertensive treatment. For patients treated for hypertension, we found a mean (95% confidence interval) decrease in systolic and diastolic blood pressure of −0.82 (−1.06 to −0.58) mm Hg and −0.89 (−1.05 to −0.73) mm Hg/yr, respectively. Factors associated with a decline in systolic blood pressure were baseline blood pressure, presence of chronic kidney disease, cardiovascular events, and the typical risk factors for cardiovascular disease. In patients with hypertension, increase in systolic blood pressure [(hazard ratio 1.18 (1.06 to 1.32) per 10 mm Hg increase], total cholesterol, smoking, age, and cumulative exposure to protease inhibitor–based and triple nucleoside regimens were associated with cardiovascular events.
Conclusions: Insufficient control of hypertension was associated with increased risk of cardiovascular events indicating the need for improved management of hypertension in HIV-infected individuals.
With the success of modern combination antiretroviral therapy (cART), HIV-infected patients have much longer life expectancy and are therefore increasingly at risk of non–AIDS-related morbidity and deaths.1–4 Individuals with chronic HIV infection present high levels of risk factors for cardiovascular diseases, such as smoking, hypertension, diabetes, and dyslipidemia.
Hypertension is among the leading risk factors for cardiovascular diseases and accounts for 6% of adult deaths worldwide. The incidence of hypertension in HV-infected populations is growing and only partly related to improved survival and the aging effect in HIV cohorts.5,6 Older HIV-infected patients develop more hypertension and other cardiovascular comorbidities than what would be expected with aging in HIV-negative individuals.7,8 The reasons for this remain unclear and may be partially related to HIV-dependent endothelial inflammatory processes or antiretroviral drugs.9–23 Some antiretroviral drugs may increase the risk of cardiovascular events independently from antiretroviral drug–induced dyslipidemia and insulin resistance, and some studies have found an association between cART and hypertension.24–28 Protease inhibitors (PIs) against HIV may induce the activation of the renin–angiotensin system.29 There are also potential pharmacokinetic and metabolic interactions between antihypertensive drugs and cART.30 However, the beneficial effects of cART by far outweigh these side effects.
Effective treatment of hypertension in HIV-infected patients independently of the cART regimen is thus very important to prevent cardiovascular morbidity and mortality. Studies from the international DAD study and the Swiss HIV Cohort Study (SHCS) show that the prevalence of hypertension in HIV-infected individuals is high with little change over time.25,31 This raises questions on the extent of hypertension control. Surprisingly only limited data are available on how well HIV-infected patients are treated for hypertension and to what extent blood pressure reduction can be achieved. We therefore investigated changes in blood pressure over time and the risk of cardiovascular events in patients with hypertension in the SHCS.
The SHCS is a multicenter, prospective cohort study with continuing enrollment of HIV-infected adults (aged ≥ 18 years).32 Enrollment in the SHCS is independent of the stage of disease, the degree of immunosuppression, or whether the individual is receiving cART. Over 15,000 HIV-infected individuals have been included in the SHCS so far, corresponding to approximately 70% of all HIV-infected individuals in Switzerland. Informed consent is obtained from all participants. Participants are followed up every 6 months at outpatient clinics and private practices and asked to provide information on sociodemographics, comorbidities, and concomitant medications. Laboratory data, including CD4 cell counts and HIV viral load, are collected at each visit.
Since April 2000, systolic and diastolic blood pressure measurements together with other cardiovascular risk factors are recorded every 6 months in the SHCS. Based on the guidelines from the European Society of Hypertension and the European Society of Cardiology,33–35 we define hypertension as systolic or diastolic blood pressure measurements above 139 or 89 mm Hg on 2 consecutive cohort visits and the presence of at least 1 cardiovascular risk factor. Cardiovascular risk factors include smoking (>1 cigarette per day), dyslipidemia (defined as a total cholesterol >6.5 mmol/L or high-density lipoprotein (HDL) cholesterol <1.0 mmol/L), family history of cardiovascular disease, diabetes (defined as a clinical diagnosis, any plasma glucose measurement >11.1 mmol/L or >7.0 mmol/L in fasting state, or taking antidiabetic drugs or insulin), and chronic kidney disease (defined as a glomerular filtration rate <50 mL/min/1.73 m2 measured by the Cockcroft–Gault equation). We define a cardiovascular event to be myocardial infarction, coronary angioplasty, bypass surgery, or stroke.
This longitudinal study includes all patients in the SHCS diagnosed with hypertension between April 1, 2000 and March 31, 2011. These patients are monitored to September 30, 2011 to ensure at least 6 months of follow-up. Patients with previous cardiovascular events, already on antihypertensive treatment, and pregnant women were excluded.
The primary outcome for this study is changes in blood pressure since starting antihypertensive treatment in treated patients. Changes in blood pressure over time are modeled using linear mixed models with repeated measurements. Separated models are fitted for systolic and diastolic blood pressure. We follow individuals from the start of antihypertensive treatment until their last recorded measurement to date or censoring (because of loss of follow-up or death).
We evaluate the impact of multiple variables on blood pressure change; these include age, gender, ethnicity, time since HIV diagnosis, total and HDL cholesterol, body mass index (BMI), waist-to-hip ratio, diabetes, cardiovascular events, chronic kidney disease, smoking, intravenous drug use (IDU) or being in a drug maintenance program, psychiatric problems (defined as being either diagnosed or treated by a psychiatrist or taking antidepressant drugs), AIDS, HIV RNA viral load, CD4 cell count, and cumulative exposure to antiretroviral drug classes. For the 92 patients with a missing date of HIV diagnosis, we use the SHCS registration date to calculate an approximate time since HIV diagnosis. We further adjust the models by baseline blood pressures to better control for the regression to the mean phenomenon36 and center effect (1 of the 7 HIV centers).
For the secondary end point analysis, we estimate the risk of a cardiovascular event and sudden cardiac death from the time of diagnosis in all patients with hypertension using time-dependent Cox proportional hazards models. The models are stratified by centers and adjusted by the same covariates as above. Blood pressures are also included as time-dependent covariates. Likewise, we explore the predictors of initiating antihypertensive treatment in this population of hypertensive HIV-infected patients, with cumulative exposure to antiretroviral drug classes being replaced by the current exposure. For each analysis, hazard ratios (HRs) and 95% confidence intervals (CIs) are presented.
All analyses and graphics are done with SAS version 9.2 (SAS Institute Inc., Cary, NC) and R version 2.15.0 (R Foundation for Statistical Computing, www.r-project.org).
During the study period, hypertension was diagnosed in 2659 of 10,361 eligible patients with at least 2 consecutive blood pressure measurements, 28 patients were excluded due to pregnancy and 36 were excluded due to past cardiovascular events. Data on blood pressure were not available in 87 patients who had at least 1-year follow-up; these patients were more likely to be IDUs, off cART, and had longer time since HIV diagnosis. Of the 2595 patients included in the study, 869 initiated antihypertensive treatment (79 patients per 1000 patient-year), of which 317 discontinued antihypertensive treatment later in the study. The median (interquartile range) systolic and diastolic blood pressure in those starting antihypertensive treatment was 145 (134–157) mm Hg and 92 (82–100) mm Hg, respectively, the follow-up was 3.7 (1.7–6.3) years, age was 49 (43–56) years, and 84% of patients were men. At the time of antihypertensive treatment initiation, 19% of patients had diabetes, 5% had experienced a cardiovascular event, and 48% were smokers; the median CD4 cell count was 467 cells per microliter (305–676); and 71% of patients had a HIV viral load <50 copies per milliliter (Table 1). Figure 1 illustrates the evolution of systolic blood pressure over time in patients initiating antihypertensive treatment. These patients had a higher mean blood pressure at baseline, and the mean change in blood pressure tended to level off after 2 years.
In multivariate models adjusted for HIV centers, patients treated for hypertension were found to have a mean decrease in systolic blood pressure of −0.82 (95% CI: −1.06 to −0.58) mm Hg per year and in diastolic blood pressure of −0.89 (−1.05 to −0.73) millimeter of mercury per year (Table 2). Systolic blood pressure increased in older patients [1.53 (0.95–2.11) millimeter of mercury per 10-year increase], men [3.32 (1.71–4.93) mm Hg compared with women], IDU or those in a drug maintenance program [1.98 (0.41–3.55) mm Hg compared with non-IDU], patients with higher total cholesterol [0.90 (0.57–1.23) mm Hg/1 mmol/L increase], higher HDL cholesterol [3.281 (2.24–4.32) mm Hg/1 mmol/L increase], higher BMI [0.46 (0.33–0.59) millimeter of mercury per 1 index increase], higher waist-to-hip ratio [0.77 (0.11–1.43) millimeter of mercury per 0.1 index increase], and viral load ≥400 copies per milliliter [2.00 (0.62–3.38) mm Hg compared with viral suppression (<50 copies per milliliter)]. Systolic blood pressure decreased in patients with longer time since HIV diagnosis [−1.37 (−2.50 to −0.25) millimeter of mercury per 10-year increase], cardiovascular events [−2.42 (−4.29 to −0.55) mm Hg], and glomerular filtration rate <50 mL/min/1.73 m2 [−3.10 (−5.19 to −1.00) mm Hg]. Similar patterns in risk factors were found for diastolic blood pressure, except that diastolic blood pressure decreased with increasing age [−1.17 (−1.57 to −0.77) millimeter of mercury per 10-year increase].
In all patients diagnosed with hypertension, 118 experienced cardiovascular events: 54 acute myocardial infarctions, 18 coronary angioplasties, 4 coronary bypass surgeries, 32 strokes, and 10 sudden cardiac deaths. In a multivariate model stratified by centers, systolic blood pressure increased the risk of cardiovascular events by a HR (95% CI) of 1.18 (1.06 to 1.32) per 10 mm Hg increase (Table 3). The risk of a cardiovascular event was also increased for older age [HR: 1.71 (95% CI: 1.39 to 2.10] per 10-year increase), higher total cholesterol [HR: 1.16 (95% CI: 1.07 to 1.26) per 1 mmol/L increase], smoking [HR: 1.95 (95% CI: 1.28 to 2.96)], longer cumulative exposure to PI [HR: 1.11 (95% CI: 1.02 to 1.21) per 1-year increase], and triple nucleoside reverse transcriptase inhibitor (NRTI) regimen [HR: 1.28 (95% CI: 1.09 to 1.49) per 1-year increase].
For all patients with confirmed hypertension, those with a cardiovascular event [HR: 7.03 (95% CI: 4.89 to 10.1)], chronic kidney disease [HR: 2.42 (95% CI: 1.54 to 3.80)], and diabetes [HR: 1.54 (95% CI: 1.28 to 1.84)] were more likely to initiate antihypertensive treatment (Table 3). Additional predictors for the initiation of antihypertensive treatment were older age, non-Caucasian ethnicity, higher BMI, advanced HIV infection, and less suppressed viral load. Patients who were off antiretroviral treatment were less likely to receive antihypertensive treatment.
In this study of HIV-infected patients with confirmed hypertension, we found a decline of systolic blood pressure over time after patients initiated antihypertensive treatment. Factors associated with a decline in systolic blood pressure for those initiating antihypertensive treatment were baseline blood pressure, the presence of established cardiovascular and chronic kidney disease, and the typical risk factors for cardiovascular disease. However, only 79 patients per 1000 patient-year initiated antihypertensive treatment after confirmed hypertension. In addition, increase in systolic blood pressure and total cholesterol, besides age, smoking, and cumulative exposure to PI and abacavir-containing triple NRTI regimens were associated with risk of a cardiovascular event.
Only few studies have investigated blood pressure control in hypertensive HIV-infected patients despite the fact that HIV itself may increase the risk of cardiovascular diseases. In the US Veterans Aging Cohort Study, the HR for acute myocardial infarction of uncontrolled systolic blood pressure above 139 mm Hg was 2.80 (95% CI: 1.57 to 4.86) and basically the same as in patients on antihypertensive drugs with a blood pressure below 140 mm Hg.37 In this study, the adjusted hazards for acute myocardial infarction were higher in HIV-infected compared with uninfected men. In a demographics-matched study from a US health care system in Boston, the adjusted hazards of ischemic stroke were higher for HIV-infected compared to HIV-negative patients. For HIV-infected patients, a higher risk of stroke was found according to HIV viral load.38 In our study, we could not confirm any association between unsuppressed viral load and the risk of a cardiovascular event. In contrast, in vitro studies indicate that HIV is a strong inducer of endothelial inflammation promoting endothelial damage, atherosclerosis, and hypertension. Injury of endothelial cell may occur by direct infection13,15,17,21–23 or activation of endothelial cell proliferation through HIV proteins and cytokines.9,11 The interruption of cART leads to an increase of hsCRP, IL-6, D-Dimers, s-VICAM-1, P-selectine, and leptin, biomarkers that are associated with endothelial inflammation and may lead to a higher risk of cardiovascular events.12,16,20 HIV-induced endothelial inflammation has been found to be associated with increased vascular stiffness10,14,19 and impaired flow mediated dilatation in arteries,18 factors known to be associated with hypertension.
However, we observed that hypertensive HIV-infected patients who had less suppressed viral load were more frequently treated and that those off antiretroviral treatment seemed to be less likely to initiate antihypertensive treatment. We may interpret this as indirect evidence that better adherence to cART may lead to better overall drug adherence. Indeed, a recent study showed that suboptimal control of HIV viremia correlates with suboptimal control of diabetes and hypertension.39
As expected, systolic blood pressure increased with older age, higher BMI, higher waist-to-hip ratio, and was higher in men than in women. Diastolic blood pressure seemed to decrease with older age, which may be related to increased arterial stiffness. This phenomenon has also been observed by the Framingham Heart Study investigators.40
For our definition of hypertension, we requested 2 consecutive blood pressure measurements above 139 mm Hg for systolic and 89 mm Hg for diastolic blood pressure. Because blood pressure is only measured biannually in the SHCS, the time between measurements is quite long. Therefore, individuals falling under our definition of hypertension are likely to have had increased blood pressure over extended periods. With this conservative definition, the incidence of individuals initiating antihypertensive treatment is surprisingly low, given the regular follow-up within the SHCS. According to the 2007 Swiss National Health Survey done by phone contact, a third of interviewees who were told to be hypertensive remained untreated.41 In a study based on repetitive random samples from the Canton Geneva, hypertension unawareness decreased from 35.9% to 17.7% but was not paralleled by a concomitant increase in hypertension treatment, which remained low (38.2%).42 Similar rates for treated hypertension have been reported in HIV-negative individuals from other settings.43–45 But recent population data from different countries all indicate increased treatment and control rates of hypertension.46–51 In our study, patients with established cardiovascular and renal disease, those of older age, advanced HIV infection, and less suppressed viral load were more likely to initiate antihypertensive treatment. Thus, clinicians caring for HIV-infected patients seem to be more inclined to treat hypertensive patients at very high cardiovascular risk of preventing relapsing cardiovascular events. Surveillance data from HIV-negative hypertensive patients indicate similar trends of higher treatment rates in individuals at higher cardiovascular risk.46,47,52–54 The mean decrease of systolic blood pressure per year in patients treated for hypertension was low but clinically relevant and would correspond to a mean decrease of −2.5 mm Hg over a median observation period of 3.7 years. In a prospective study with high-risk patients, a blood pressure reduction in this magnitude could significantly reduce cardiovascular end points.55 Extrapolation from observational and clinical trial data indicates that a long-term reduction of the mean population blood pressure of −7 mm Hg by treating all individuals at low absolute risk would reduce the occurrence of major cardiovascular events by 26% in the following 10 years.56,57
Increased systolic blood pressure in our cohort was associated with an increased risk of cardiovascular events. We also confirmed in this population an association between cumulative exposure to PI and triple NRTI and increased risk of a cardiovascular event as previously shown in case–control study from the SHCS and the large DAD cohort study.58–60
There are several limitations of this study. The SHCS does not collect specific information of the type and combination of used antihypertensive drugs. Hypothetically, metabolic side effects might be amplified by the use of antihypertensive drugs such as diuretics and beta-blockers and lessen the cardiovascular benefits of lowering blood pressure.61–65 Nevertheless, the main goal of antihypertensive treatment is to lower blood pressure, as this has clearly been associated with lower morbidity and mortality.35 Blood pressure measurements in the SHCS are not standardized, and for example, information on 24-hour blood pressure measurements for the exclusion of white coat hypertension is missing. There was a center effect in blood pressure measurement with end digit preferences that may be related to imprecise reading, rounding documentation of blood pressure, or the use of different blood pressure measuring devices such as manual sphygmomanometers or digital devices. Over the years with the more widespread use of electronic devices, we noted less end digit preferences. For these reasons, we decide to model blood pressure change over time and not to report rates of individuals achieving blood pressure target values. In addition, many HIV-infected patients in the SHCS are also treated by general practitioners, and other specialists and infectious disease specialists may delegate or consider the treatment of cardiovascular risk factor management as not their domain. Although listing of antihypertensive drugs for SHCS patients at biannual visits is mandatory, underreporting may still occur. We lack data on HIV-infected patients that are mainly managed by HIV specialists.
This study has several strengths. The SHCS is not focused on specific risk groups and includes a fairly high proportion of female patients and patients from non-European ethnic background. The cohort has an excellent follow-up and continued repetitive measurement of blood pressure allowed to model blood pressure over time using a time-updated model. To better control for the regression to the mean phenomenon, we based our inclusion criteria for patient selection on 2 consecutive measurements that were taken 6 months apart; hence, the measurement variability is reduced. End point assessment for cardiovascular events was done according to the DAD protocol, which is a further strength of this investigation.
In conclusion, in HIV-infected hypertensive patients treated for hypertension in the SHCS, we find a decline in systolic blood pressure over time. Risk factors for hypertension and insufficient control of blood pressure for individuals in this cohort are not different from those of HIV-negative hypertensive individuals. Indirect evidence suggests that HIV-infected individuals in Switzerland are not a neglected population in regard with the management of hypertension compared with HIV-negative individuals. However, clinicians caring for HIV-infected patients should consider that HIV-infected patients may be at increased risk of the development of chronic kidney disease and cardiovascular events compared with HIV-negative individuals.25 Although HIV-infected patients at high cardiovascular risk were more likely to receive antihypertensive treatment, our study shows that many patients remain untreated or insufficiently treated for hypertension and at increased risk of a cardiovascular event. Recent evidence from the NHANES surveys from the United States underlines that better control of cardiovascular risk factors may be achieved and is associated with decreased cardiovascular mortality.66 Therefore, more aggressive treatment and better management of hypertension are urgently needed in HIV-infected patients.
The members of the Swiss HIV Cohort Study are J. Barth, M. Battegay, E. Bernasconi, J. Böni, H. C. Bucher, C. Burton-Jeangros, A. Calmy, M. Cavassini, C. Cellerai, M. Egger, L. Elzi, J. Fehr, J. Fellay, M. Flepp, P. Francioli (President of the SHCS), H. Furrer (Chairman of the Clinical and Laboratory Committee), C. A. Fux, M. Gorgievski, H. Günthard (Chairman of the Scientific Board), D. Haerry (deputy of Positive Council), B. Hasse, H. H. Hirsch, B. Hirschel, I. Hösli, C. Kahlert, L. Kaiser, O. Keiser, C. Kind, T. Klimkait, H. Kovari, B. Ledergerber, G. Martinetti, B. Martinez de Tejada, K. Metzner, N. Müller, D. Nadal, G. Pantaleo, A. Rauch, S. Regenass, M. Rickenbach (Head of Data Center), C. Rudin (Chairman of the Mother & Child Substudy), P. Schmid, D. Schultze, F. Schöni-Affolter, J. Schüpbach, R. Speck, P. Taffé, P. Tarr, A. Telenti, A. Trkola, P. Vernazza, R. Weber, S. Yerly.
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HIV infection; antiretroviral therapy; hypertension; cardiovascular event; risk factor
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