Isolated Nocturnal Hypertension in People Living With HIV: Do We Need HIV-Specific Guidelines for Hypertension Diagnosis?

Cardiovascular disease (CVD) is emerging as the leading cause of early mortality among people living with HIV (PLWH). In PLWH, the incidence of CVD is more than double that of the general population and CVD causes nearly 40% of premature deaths in PLWH.¹ The higher risk of CVD in PLWH is not fully explained by traditional risk factors such as clinic blood pressure.¹

The higher incidence of CVD observed in PLWH may be related to abnormal diurnal variation in blood pressure as quantified by ambulatory blood pressure monitoring. We know that blood pressure should decline, or “dip,” during the night. Compared with the general population, PLWH may have a higher prevalence of nocturnal non-dipping of blood pressure,^2,3 nocturnal hypertension,² and masked hypertension.⁴ Ambulatory blood pressure is more strongly associated with CVD events and mortality than clinic blood pressure.^5,6 Nighttime blood pressure is a particularly strong predictor of CVD events, CVD mortality, and overall mortality even after adjusting for office blood pressure.⁶ A 14-year, multinational population-based cohort study found that nighttime blood pressure was the strongest independent predictor of both CVD events and overall mortality in a diverse group of adults.⁵ Therefore, these abnormalities in nighttime blood pressure in PLWH are of great concern.

Isolated nocturnal hypertension (INH) is a specific, clinically important ambulatory blood pressure phenotype. INH is defined as an elevated nighttime blood pressure (≥120/70 mm Hg) in the presence of normal daytime blood pressure (<135/85 mm Hg) as measured by ambulatory blood pressure monitoring.⁷ INH is the most common type of masked hypertension in the general population and is found in over a one-third of patients with nocturnal hypertension.⁸ INH has been found to be independently associated with arterial stiffness, left ventricular hypertrophy, and silent cerebrovascular lesions independent of clinic blood pressure.⁹ Yet INH often remains “hidden in the dark,” since it cannot be diagnosed through clinic or home blood pressure measurements.^6,8

In this issue of the American Journal of Hypertension, Zanuzzi et al. report that INH was present in 20% of PLWH randomly selected from a large HIV center in Argentina. This cross-sectional study of 66 PLWH was conducted between 2013 and 2014. Nocturnal blood pressure abnormalities were extremely common in this study population. Nearly half of participants had nocturnal hypertension and two-thirds had nocturnal non-dipping of blood pressure.¹⁰ These findings confirm and extend the only other published report of INH in PLWH. In this prior cross-sectional study of 174 PLWH from Spain, the prevalence of INH was 23%.¹¹

The 20%–23% prevalence of INH in PLWH from Argentina and Spain is 2-fold higher than those observed in the general population (6%–11%)¹² and similar to the prevalence reported in patients with chronic kidney disease.¹³ These data suggest that HIV could be a major risk factor for INH on the same order as kidney disease.

The possible causes of elevated nocturnal blood pressure among PLWH—as manifest by INH, nocturnal hypertension, and nocturnal non-dipping—remain unclear. In a systematic review, Kent et al. proposed that elevated nocturnal blood pressure in PLWH may be due to HIV-related stigma, stress, and depression but that HIV infection, HIV-related chronic inflammation and antiretroviral therapy might also contribute.² Zanuzzi et al. report that INH in PLWH in Argentina was independently associated with obesity, a sedentary lifestyle, elevated plasma potassium, and elevated plasma high-sensitivity C-reactive protein (hs-CRP).¹⁰ Neither viral load nor duration of antiretroviral therapy were associated with INH in this study. These findings from Argentina are in line with factors associated with elevated blood pressure in other populations of PLWH.^1,14

The current study from Argentina and the prior study of INH in PLWH in Spain share similar weaknesses which point toward future directions for research. Both studies were small (66 and 174 participants) and neither included an HIV-uninfected comparison group. Neither study included Asian or African participants. This is important because people of Asian and African ancestry people are thought to have a higher prevalence of nocturnal hypertension^12,15 and 26 million (66%) of the estimated 39 million PLWH worldwide live in Africa. Also, sleep was not assessed in this study even though sleep disorders are common in PLWH,¹⁶ and closely linked with nocturnal blood pressure. In addition, the diagnosis of INH was not confirmed with repeat ambulatory blood pressure and neither study included longitudinal follow-up to link INH to the onset of CVD. Therefore, it is impossible to conclude whether INH might be a benign and/or transient phenomenon in PLWH.

Ambulatory blood pressure monitoring might be a particularly valuable diagnostic tool for preventing CVD in PLWH given: (i) the residual CVD risk that exists ever after accounting for clinic blood pressure and (ii) the high rates of masked and nocturnal hypertension that have been reported in PLWH.⁴ Despite these potential benefits of ambulatory blood pressure monitoring in PLWH, this diagnostic tool remains massively underutilized on the continent where most PLWH reside.⁷ Even in the United States and Europe, ambulatory blood pressure monitoring is rarely deployed for the diagnosis of hypertension in PLWH.^1,2 New technology is needed to make ambulatory blood pressure monitoring more affordable and accessible. We must also develop equitable and inclusive strategies and policies to encourage the use of ambulatory blood pressure monitoring among PLWH.

This study also points to the need for HIV-specific guidelines for managing hypertension in PLWH. Such guidelines might address: (i) more aggressive hypertension diagnostic algorithms with an emphasis on application of ambulatory blood pressure monitoring in PLWH with borderline blood pressure, (ii) initiation of blood pressure medication at lower blood pressure thresholds for PLWH,¹⁷ (iii) preferential use of specific antihypertensive agents,¹⁸ and/or (iv) guidelines for assessing sleep duration, timing, and sleep apnea in PLWH at risk. Nighttime administration of antihypertensive among PLWH with elevated nocturnal blood pressure could also be considered.

In addition to new guidelines, we also need implementation research to guide the deployment of new hypertension management guidelines into HIV care. This is particularly true for resource limited countries and communities. In Africa, hypertension guidelines will need to be integrated into existing national HIV primary care programs.¹⁹ Access to sleep medicine services will also need to be expanded together with psychotherapy and medications for HIV-related anxiety and depression.

We have new hope that HIV-specific strategies for CVD prevention may improve the long-term health of PLWH in the light of the recently published REPRIEVE trial. REPRIEVE—which demonstrated that earlier initiation of statin therapy in PLWH could significantly reduce CVD events—was the first large randomized clinical trial to demonstrate that an HIV-specific strategy could reduce CVD in PLWH.²⁰ The next step in this journey toward longer and healthier lives in PLWH might involve HIV-specific strategies for diagnosing and treating hypertension.