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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