Blood pressure level impacts risk of death among HIV seropositive adults in Kenya: a retrospective analysis of electronic health records

In North America and Europe, cardiovascular disease is the second most common cause of death among HIV seropositive (+) individuals after acquired immunodeficiency syndrome (AIDS)-related mortality [1]. This trend has been accompanied by a shift in the long-term care of HIV+ patients to include attention to cardiovascular risk [2, 3]. Observational studies from around the globe support the association between HIV infection and increased risk of cardiovascular disease, however, these studies have largely not included patients from developing countries [4–7].

Most people with human immunodeficiency virus (HIV) infection live in sub-Saharan Africa (SSA). Sixty-nine percent (23.5 million of 34 million) of all people infected with HIV worldwide and the majority of HIV-related deaths are in SSA [8]. Infectious and immunological factors have usually been associated with the highest risk of death in people living with HIV in SSA [9, 10]. However, HIV+ individuals without AIDS in SSA can now achieve a near normal life expectancy and hypertension is not uncommon [11, 12]. The degree to which high blood pressure is related to mortality in HIV+ patients in the region has not been specifically addressed [10]. This may be related to under-recognition of the magnitude of the risk of death associated with cardiovascular risk factors among HIV+ individuals in SSA.

The relationship between blood pressure level and mortality in HIV+ patients may have important policy implications as HIV+ individuals age and programs in SSA expand their scope to address the important overlap between communicable and non-communicable diseases [13]. Therefore, the aim of this study was to describe the relationship between HIV infection, blood pressure level, and death in a cohort of HIV+ adults without AIDS from a large HIV treatment program in western Kenya. By so doing, our objective was to describe the overall relationship and identify important mortality differences according to gender and clinical stage of HIV.

Among women, there were 1351 deaths in 75,786 person years (py) of follow up (mortality rate 1.8/100 py). Among men, there were 966 deaths in 25,369 py of follow up (mortality rate 3.8/100 py). With respect to blood pressure, within gender, crude mortality rates are substantially higher for those in the lowest SBP and DBP categories compared to all other categories. The difference is particularly pronounced among men, where mortality rate is 10.7/100 py for those with SBP <100 and 16.4/100 py for those with DBP <60 mmHg.

Figure 2 shows age-adjusted survival curves stratified by SBP and DBP categories, separately for each gender. The curves depict expected survival probabilities when age is fixed at 35 years demonstrating that those with low DBP and SBP have the highest age adjusted mortality rates. Additional files 2 and 3 (Figures S3 and S4) are smoothed linear spline curves applied to the unweighted sample of all individuals having baseline blood pressures showing the relationship between blood pressure and mortality rate among men and women with and without advanced HIV.

Chronic, non-HIV related conditions are an increasingly important part of HIV management, a trend that has historically been underappreciated [19]. While the burden of high blood pressure among Africans living with HIV has been highlighted, the impact of blood pressure on important clinical endpoints has not been well established and therefore has not routinely been a focus of treatment in HIV programs in the region [12, 20]. With this gap in the literature in mind, we have shown that low enrollment SBP or DBP is associated with a high mortality risk among HIV+ patients. There was also a relationship between higher initial SBP and mortality in men without advanced HIV. In adjusted analyses, the effect of high blood pressure was smaller than the effect of low blood pressure.

The greatest mortality risks in the present analysis were related to low blood pressure. In addition to advanced disease stage, other well-documented reasons for low blood pressure in HIV+ patients include adrenal insufficiency, autonomic dysfunction, concomitant infections, and the effects of bacterial translocation among others [21–23]. The cause of low blood pressure was not identifiable in this study, however, these factors as well as concomitant illness may have contributed to the observed low blood pressure. Lower blood pressure has also been observed in patients with more advanced HIV disease [24] and we posit this explanation in this analysis based on the deranged parameters of body mass index, hemoglobin and CD4 count in those with the lowest blood pressure. The mortality risk, however, was large and indicates the need to explore concomitant clinical factors as well as cause of death in this population. Such data and relatively simple measures such as blood pressure measurement are only recently beginning to be explored in HIV cohorts on the continent, highlighting a strength and relevance of this analysis [25].

Western literature supports a relationship between higher SBP and mortality in HIV+ men. In the Multicenter AIDS Cohort, Seaberg et al., demonstrated that the prevalence of systolic hypertension among men taking ART for less than two years was similar to that of HIV seronegative (-) men, but was nearly two-fold higher after two to five years of ART and five years or more of ART [26]. Other studies support the relationship between HIV positivity and higher blood pressure, but this is still debated [27–29]. Compared to Western countries, there has been relatively little attention paid to the overlap between non-communicable cardiovascular diseases and HIV in SSA. In a large systematic review and meta-analysis (50 studies including 38 from SSA) of early mortality in adults initiating ART in low- and middle-income countries, blood pressure was not reported as a covariate of interest in any of the studies [10].

Data from the SSA region regarding blood pressure, however, are slowly emerging. The overall rate of hypertension among HIV+ patients in SSA is estimated to be 8-19%, and slightly higher among men compared to women [12]. In Kenya, a program showed that when people are screened for HIV and non-communicable diseases simultaneously, HIV+ people had higher rates of hypertension (32%) than those who were HIV- (19%) [30]. Similar findings are reported from Tanzania, Botswana, and Nigeria while in our analysis hypertension was present in less than 10% of the population [31–33]. A systematic review and meta-analysis of the association between HIV and cardiometabolic traits, however, suggests that HIV+ patients have, on average, lower blood pressure than their HIV- counterparts [34]. It is noteworthy that the studies included in this review vary in patient population, method of screening, selection of patients and definitions of outcomes resulting in an unresolved relationship between blood pressure and HIV. Given the size of our HIV care program, we believe the observed relationship between high blood pressure and mortality may be generalizable to the region, however, country-specific data comparing HIV+ to HIV- patients are needed to put the magnitude of the issue in a relevant context. Both high and low blood pressure impact mortality in these patients suggesting that addressing blood pressure in HIV+ patients in SSA is potentially a lost opportunity to modify health and impact mortality.

The differences in mortality risk between men and women warrant further exploration. The reasons for the observed higher mortality risk related to high blood pressure among men compared to women may be related to a true sex-related difference in the impact of high blood pressure or reflect other factors that vary according to sex including less health-seeking behavior among men or higher burden of other cardiovascular risk factors (e.g., tobacco smoking) among men [35]. Moreover, most of the women in this analysis were of pre-menopausal age and may therefore carry lower risk of cardiovascular disease than men. Prospective analyses that can control for known sex-based differences will be able to elucidate whether higher blood pressure among HIV+ men carries a greater mortality risk than among women.

Some limitations of our study should be considered. This was a retrospective analysis of clinical data and variables, including blood pressure, that were not measured routinely in every patient or in a standard, protocol-driven manner. Our analysis is therefore limited by a selection bias potentially introduced at the time of the clinical encounter and our observations do not confirm causality. We had a significant proportion of patients missing data and while this is often the situation in reality, we addressed this by using IPW to account for differences in mortality between those with and without missing covariates. Our weighting approach resulted in similar survival distributions between those with fully observed and partially observed covariates and supported its use for fitting the proportional hazards models. Incomplete data is not uncommon in HIV treatment programs in SSA and our approach represents one method for addressing this phenomenon [11]. Information on diabetes, smoking or use of cardiovascular medications was also not routinely measured during this time. Further, cause of death information was not available for this cohort and we are therefore limited in our ability to comment on the mechanism of the association between BP and mortality in this analysis. Given than non-communicable cardiovascular causes of death present at a younger age in populations earlier in the epidemiologic transition, it seems necessary to investigate these associations as well as possible mechanisms in HIV+ patients. Data from the region using verbal autopsy, however, show that non-communicable diseases account for between 2 and 10% of deaths among HIV+ individuals on ART [36, 37].

In summary, while cardiovascular risk factor levels remain low in SSA in general and life expectancy among HIV+ individuals nears 80% of normal, a rare opportunity currently exists to understand and decrease or prevent cardiovascular risk in a population still on the cusp of a non-communicable disease epidemic. Literature from developed countries support a relationship between HIV and cardiovascular disease risk and the burden of HIV in SSA calls for more attention to these comorbidities. Using clinical data from a large HIV treatment program in western Kenya, we have demonstrated that low and high blood pressures in HIV+ patients are important predictors of mortality with low blood pressure carrying the greatest mortality risk. Of particular clinical relevance is the finding that high blood pressure is associated with higher mortality risk among patients whose HIV disease is not advanced. Therapy for high blood pressure should be instituted when indicated. Patients with low blood pressure should undergo a thorough assessment to uncover and reverse the causes. To our knowledge, this is one of the first and largest reports from the region indicating this relationship and highlights the need to address cardiovascular diseases in this population, especially among patients without advanced HIV. Programs in SSA that are narrowly focused on HIV treatment alone may be missing an important opportunity to modify health.