Open Access
01.07.2019 | Inflammation and Cardiovascular Diseases (A Kirabo, Section Editor)
Patho-immune Mechanisms of Hypertension in HIV: a Systematic and Thematic Review
verfasst von:
Sepiso K. Masenga, Benson M. Hamooya, Selestine Nzala, Geoffrey Kwenda, Douglas C. Heimburger, Wilbroad Mutale, Sody M. Munsaka, John R. Koethe, Annet Kirabo
To systematically review recent findings on the role of immune cell activation in the pathogenesis of hypertension in people living with HIV (PLWH) and compare studies from Sub-Saharan Africa with what is reported in the USA and European literature according to guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Recent Findings
PLWH have an increased risk for development of hypertension and cardiovascular disease. Chronic immune activation contributes to hypertension but the inflammatory milieu that predisposes PLWH to hypertension is poorly understood. We identified 45 relevant studies from 13 unique African countries. The prevalence of hypertension in PLWH on antiretroviral therapy (ART) and the ART-naive PLWH ranged from 6 to 50% and 2 to 41%, respectively. Interleukin (IL)-17A, interferon (IFN)-γ, and higher CD4+ T cell counts were associated with hypertension in ART-treated participants.
Summary
Targeting adaptive immune activation could provide improved care for hypertensive PLWH. Further research is needed to characterize the inflammatory milieu contributing to hypertension in PLWH especially in African populations where the global burden of HIV is the highest.
Hinweise
This article is part of the Topical Collection on Inflammation and Cardiovascular Diseases
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Introduction
The introduction of antiretroviral therapy (ART) has improved survival among people living with HIV (PLWH), but this success is accompanied by a high burden of cardiovascular disease [1‐3]. Hypertension is a major risk factor to cardiovascular disease and its prevalence is higher in PLWH despite viral suppression by ART [4]. The mechanisms contributing to hypertension and cardiovascular disease in PLWH are not fully understood.
A heightened systemic inflammatory process including activation of the innate and adaptive immune systems contributes to the development of hypertension in the general population and in experimental animal studies [5‐7]. However, it is unknown which innate and adaptive immune factors are most closely linked to hypertension in PLWH. At present, much of our understanding of the role of immune cell activation in the pathogenesis of hypertension comes from experimental animal and human studies in the HIV-negative context, but similar inflammatory biomarkers implicated in these HIV-negative studies have also been associated with hypertension in HIV infection. In this review, we present the current understanding on HIV, hypertension, and immune activation and how these may be related and highlight gaps and the need for further studies. We review studies conducted in Sub-Saharan Africa where the global HIV infection burden is the highest. We also performed a comparative analysis contrasting studies from Sub-Saharan Africa with what is reported in the USA and European literature.
Anzeige
The aim of our current study was to estimate the prevalence of hypertension in PLWH from African studies, identify inflammatory markers or markers of immune activation associated with hypertension in antiretroviral (ART)-treated HIV-positive individuals, and to explore the possible mechanistic interaction between immune activation, hypertension, and HIV in cohorts from Sub-Saharan Africa and contrast with European and US cohorts.
Methods
We followed guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [8, 9].
Eligibility Criteria for Studies Included in the Review
We considered studies on HIV-positive human subjects with or without the HIV-negative population as controls. For exposure and outcome variables, we considered HIV infection as the exposure and our outcome measures were hypertension or blood pressure, inflammation, and/or immune activation. Only published articles in peer-reviewed journals were considered. Articles in languages other than English were not considered. We only included studies from Sub-Saharan African, USA, and European HIV-positive populations that reported on hypertension and HIV excluding studies that did not report HIV at all. We also excluded studies reporting opportunistic infections and other coinfections to reduce bias when deducting on the contribution of HIV on hypertension. In case of duplicate publications, the article with more complete data was included. Extracted information focused on study design, population, sample size, country where study was conducted, and details of findings with conclusions. The source of research articles was derived from Pubmed, Medline, google scholar, and google search. Dates of coverage were not specified to filter studies addressing hypertension and inflammation or immune activation in HIV owing to the scarcity of published studies. Other articles were identified from reference lists of related studies from the included study. Search terms that were used in databases employed the use of Boolean operators “AND,” “OR,” and “NOT” to refine our search by combining or limiting terms. The key terms used to search for articles were “hypertension,” “blood pressure,” “immune activation,” “inflammation,” “Africa,” and “HIV.”
Studies were screened based on abstract information that reported HIV or/and inflammation or immune activation and hypertension or blood pressure. A full article was then obtained and screened to ensure eligibility. The PRISMA 2009 Flow Diagrams for article identification, screening, eligibility, and inclusion in Sub-Saharan African and the Western populations are shown in Supplementary Figures 1 and 2 found at the following link: https://figshare.com/s/38ff86137d00153423ac. For data extraction, we used a data collection form that identifies the author, study, population, sample size, methods, findings, and limitations.
Anzeige
Risk of bias was assessed by two reviewers. For the criteria used to assess internal validity of included studies, we made use of the Cochrane Risk of Bias tool, paying attention especially to parts such as completeness of outcome data, selective outcome reporting, reporting bias, and any other bias that may affect the exposure-outcome relationship. For any disagreements between the reviewers over the risk of bias in particular studies, this was resolved by discussion, with involvement of a third review author where necessary.
Data Synthesis
We did not conduct a meta-analysis. We only conducted a systematic thematic review due to the qualitative nature of our study and due to excessive heterogeneity of population, outcome, or methodology. To assist with the result and discussion write-ups, we constructed summary tables and provided a narrative synthesis (thematic or content analysis). This includes investigation of the similarities and the differences between the findings of different studies, as well as exploration of patterns in the data. Reasons for similarities and differences in the findings were also explored systematically. Studies were grouped based on reported parameters. We also considered how the results of studies might be affected by factors such as methodological differences, variable characteristics of the populations studied, or interventions investigated. Conceptual models were used to explore relationships and patterns from study findings and we related the findings to existing concepts from animal models to generate hypotheses and the need for further studies.
Results
Characteristics of the Studies
We performed a systematic review of studies on HIV, hypertension, and immunity from countries in Sub-Saharan Africa, USA, and Europe. For Sub-Saharan Africa studies shown in Table 1, we included 45 studies from 13 countries. Of the 45 studies, 27 were cross-sectional, 15 were prospective, and three were retrospective. Most of the studies (35) reported on both hypertension and HIV. The prevalence of hypertension was highest in the HIV-positive group on ART (ranging from 6.4 to 50.2%) followed by HIV-negative controls (13.7 to 44%). ART-naive patients recorded the lowest prevalence ranging from 2 to 41% by group comparisons. The prevalence differences of groups within studies were highest between ART treated and ART-naive HIV-positive groups (35.7) followed by ART treated and HIV-negative group (18.7) with the least difference in magnitude between HIV negative and ART-naive groups.
Table 1
Characteristics of studies included in the Sub-Saharan African studies
Study characteristics
Number (n) or percentage (%)
Number of studies included
45
Number of African countries where the studies were conducted
13
Number of types of studies
3
Studies reporting on inflammation plus hypertension plus HIV only
5
Studies reporting on hypertension plus HIV only
35
Studies reporting on HIV plus immune activation/inflammation
5
Studies reporting on inflammation plus hypertension in African populations
0
Overall prevalence of HTN in PLWH on ART (% range)
6.4–50.2
Overall prevalence of HTN in ART-naive PLWH (% range)
2–41
Overall prevalence of HTN in HIV-negative population (% range)
13.7–44
HTN prevalence percentage differences within studies, range (│magnitude│)
PLWH on ART minus ART naive
− 12.3 to 23.4 (│35.7│)
PLWH on ART minus HIV negative
− 6.3 to 12.4 (│18.7│)
HIV negative minus ART naive
− 5.3 to 11 (│16.3│)
HTN, hypertension; HIV, human immune deficiency virus; ART, antiretroviral therapy; PLWH, people living with HIV
When we included USA and European studies, shown in Supplementary Table 1 found at the following link: https://figshare.com/s/38ff86137d00153423ac, the global prevalence of hypertension in PLWH ranged from 4 to 57% (van Ziest et al. 2017) [10]. Hypertension was more prevalent in HIV uninfected (71%) versus HIV infected (57%) in a large longitudinal study by Armah et al. [11]. HIV-infected veterans with HIV-1 RNA ≥ 500 copies/mL or CD4 count < 200 cells/μL had a significantly higher prevalence of elevated IL-6 and D-dimer after adjusting for comorbidities and had significantly higher prevalence of elevated sCD14 compared to uninfected veterans. Manner et al. [12] reported prevalence of 35% hypertension in HIV-infected individuals and the prevalence did not change during the follow-up time (3.4 ± 0.8 years). CD4 T cell count < 50 cells/μL and increased duration of ART were independent predictors of sustained hypertension throughout the study period. Older age, male gender, BMI > 25 kg/m2, and baseline CD4 cell count ≥ 200 cells/μL were also independent predictors of sustained hypertension. Markers of microbial translocation predicted hypertension in HIV-infected individuals. Manner et al. found that both LPS and sCD14 independently predicted subsequent blood pressure levels after adjustment for age and gender [12]. These results suggest that ART may act as a contributing factor to inflammation and the increased prevalence of hypertension in the PLWH.
Higher Levels of IL-17A, IFN-γ, and CD4+ T Cells Are Associated with Hypertension in HIV
We found that among studies reporting on both inflammation, immunity, and hypertension in HIV (Table 2), higher levels of IL-17A, IFN-γ, [13••], and CD4+ T cell count (Peck et al.) [4] were significantly associated with hypertension in ART treated HIV-positive individuals. The cross-section study by Chepchirchir et al. reported that females were more likely to have higher IL-17A levels than males and IL-17A was affected by BMI but not stress levels, ART, World Health Organization (WHO) stage, and CD4+ count [13••]. However, inflammatory cytokines IL-2, IL-6, IL-8, tumor necrosis factor alpha (TNF-α), and anti-inflammatory cytokines IL-4 and IL-10 were not associated with hypertension. The cross-section study by Peck et al. reported higher cases of hypertension among PLWH on ART [28.7% (43/150)] compared to ART-naive participants [5.3% (8/151)]; however, the prevalence was higher in HIV-negative patients [16.3% (25/153)] compared to ART-naive HIV-positive patients. The inflammatory markers, C-reactive protein (CRP), and IL-6 in the prospective study by Fourie et al. where the three participant groups had comparable blood pressures did not differ between HIV positive on ART, ART naive, and HIV-negative groups. In another prospective study by Okello et al., blood pressure increases were reported in the first 6 months of ART initiation then plateaued. Traditional risk factors including older age, male gender, African-American, higher body mass index (BMI), central obesity, previous cardiovascular events, chronic kidney disease, family history of hypertension and cardiovascular disease, diabetes, and dyslipidemia rather than immune activation were associated with incident hypertension in this study. Borkum et al. reported high levels of inflammation and non-dipping blood pressure [14••].
Table 2
Characteristics and findings of studies reporting on inflammation, hypertension, and HIV
Cross-section study conducted in Kenya among PLHIV
126 HIV-positive with and without hypertension
• HTN prevalence was 23.2%
• IL-17A was associated with hypertension in HIV {HTN 75.51 ± 84.89 versus normotensives 42.23 ± 64.40; CI 6.81–59.77, p < 0.001 and females were more likely to have higher IL-17A levels than males in HIV (p < 0.001)
• IL-17A was affected by BMI r(124) = 0.223 p = 0.070 but not stress levels, ART, WHO stage and CD4+ count
• IFN-γ {HTN 6.87 ± 35.66; normotensives 0.00 ± 0.00 CI − 1.96–15.71, p = 0.003} correlated negatively with hypertension status (rs = − 0.217, p < 0.015)
• IL-4,-2,-6,-8,-10, TNFα were not associated with hypertension
• Monitoring and analysis of cytokine expression may help to predict patients’ pathways in their response to cART therapy and risk of metabolic disorders
• IFNγ is potentially useful in determining risk of developing hypertension in this population
• Mechanism of interaction between hypertension and inflammation or immune activation not very explicit
Cross-sectional study conducted in Tanzania among PLHIV
454 participants: HIV+ on ART, ART-naive HIV+ and HIV-negative controls
• Prevalence of HTN in HIV negative was 16.3% (25/153)
• Prevalence of HTN in HIV+ on ART was 28.7 (43/150) was the highest (p = 0.01) among the groups with higher odds HTN even after adjustment (odds ratio (OR) = 2.19 (1.18 to 4.05), p = 0.01)
• Prevalence of HTN in ART-naive HIV+ was 5.3% (8/151), and lowest among group (p = 0.003) with lower odds of HTN even after adjustment (OR = 0.35 (0.15 to 0.84), p = 0.02)
• The prevalence HTN was lowest in group with the lowest average CD4+ T cell count (HIV-infected ART naive) and highest in the group in which the CD4+ T cell count had been low and had then been reconstituted in the setting of ART
• In the HIV+ group, higher CD4+ T cell counts were associated with more hypertension and higher blood pressures
• Age, vigorous work, current alcohol use, and BMI were all associated with hypertension
• Only PI use was associated with HTN
• Among the HIV-infected adults with HTN, 75% were undiagnosed, 85% were untreated, and > 95% were uncontrolled
• HIV-infected adults with hypertension were rarely aware of their diagnosis but often have evidence of kidney disease
• It was unknown whether chronic inflammation accelerates HTN
• High prevalence of hypertension among HIV-infected adults on ART could be related to dysregulated inflammation due to immune reconstitution
• Mechanism of interaction between hypertension and inflammation or immune activation not explicit
• Systolic BP increased by 9.6 mmHg/year (95% CI 7.3–11.8) in the first 6 months of ART, then plateaued
• Male gender, overweight, and a CD4 count < 100 cells were associated with incident hypertension
• Blood pressure increases early after ART initiation in Ugandans. Traditional risk factors, rather than immune activation were associated with incident hypertension in this population
• Only sCD14, sCD163 (immune activation markers), and IL-6 (inflammatory marker) were examined
• Mechanism of interaction between hypertension and inflammation or immune activation not explicit
Cross-sectional study conducted among South African blacks
67 HIV-positive participants on ART > 5 years
• Prevalence of non-dipping BP was 65%
• High levels of inflammation (hsCRP)
• There was no association on multivariable analysis between dipping status and traditional risk factors for non-dipping BP, such as obesity, autonomic dysfunction, and older age
• 91% (n = 61) were females
• Inflammation was only assessed using hsCRP
• Mechanism of interaction between hypertension and inflammation or immune activation not explicit
PLHIV, people living with HIV; HTN, hypertension; HIV, human immunodeficiency virus; BP, blood pressure; CRP, C-reactive protein; ART, antiretroviral therapy; PI, protease inhibitors; IL, interleukin; BMI, body mass index; CI, confidence interval; TNFα, tumor necrosis factor alpha; IFNγ, interferon gamma; WHO, World Health Organization; cART, combinational ART; sCD14, soluble CD14; sCD163, soluble CD163; hsCRP, high-sensitivity C-reactive protein
Prevalence of Hypertension Is Higher in ART-Treated PLWH
As shown in Table 3, hypertension prevalence was mostly higher in men than women [15‐17] and higher among ART treated versus ART naive (28.7% vs 5.3%; 17% vs 2%; 30 vs 21.9% and 38% vs 19%, respectively) [17, 18]. However, one study [22] reported contradictory findings (ART vs ART naive, 12.3 vs 19%). In another study, [17] reported higher prevalence of hypertension in ART treated group (28.7%) compared to the HIV-negative controls (16.3%) but two studies [22, 25] reported the opposite (41% vs 44% and 12.3% vs 13.7%, respectively). Peck et al. reported higher prevalence of hypertension in HIV negative vs ART-naive HIV-positive group (16.3% vs 5.3%) [17]. On the contrary, Ogunmola et al. reported lower prevalence of hypertension in HIV negative vs ART-naive HIV-positive group (13.7% vs 19%, respectively). Association between hypertension and traditional risk factors including specific ART regimens varied between studies.
Table 3
Characteristics and findings of studies reporting on hypertension and HIV
Cross-sectional study conducted in Uganda and Zimbabwe among PLWH
3316
Prevalence of systolic and diastolic hypertension was 21.3% and 19.0% for older adults; and 9.2% and 3.5% for younger adults with HIV (both, p < 0.001)
Immune mechanism or inflammation as it relates to hypertension was not addressed
Prospective study conducted in South Africa among PLWH
137 participants: 66 HIV+ on ART and 71 HIV+ ART-naive participants
HIV+ on ART had higher pulse pressure (13.3%; p = 0.004), systolic blood pressure (4.5%; p = 0.029), and CD4 cell count (9.2%; p = 0.009) levels over 5 years
Immune mechanism or inflammation as it relates to hypertension was not addressed
Prospective study; randomized, open-label ART trials among 7 African countries (South Africa; Kenya; Zimbabwe, Botswana, Zambia, Malawi, and Uganda)/population included HIV+ women only with immunocompromised CD < 200
741
Over 144 weeks NVP compared to LPV/r group had greater mean increases in BP (diastolic BP 22.7% vs. 6.5%)
Immune mechanism or inflammation as it relates to hypertension was not addressed
• The prevalence of hypertension was 26.2% and was high among those on ART (30.0% vs 21.9%, p = 0.010)
• Aged > 40 years (AOR = 2.52, 95% CI 1.37–4.63), abnormal waist circumference (AOR = 2.37 95% CI 1.13–5.00), overweight/obesity (AOR = 2.71, 95% CI 1.26–5.84), and male sex (AOR = 1.17, 1.02–4.20) were the predictors of hypertension among patients on ART while raised total cholesterol (AOR = 1.47 (1.01–2.21) and being aged > 40 years (AOR = 3.42, 95% CI 2.06–5.70) were predictors for hypertension among ART-naive patients
Immune mechanism or inflammation as it relates to hypertension was not addressed
• Systolic and diastolic blood pressure increased significantly and the proportion of participants with hypertension increased from 3.9 to 15.5% (p < 0.001)
• Long-term exposure to ART, increased in hypertension
• Stavudine and efavirenz and nevirapine were significantly associated with hypertension
Immune mechanism or inflammation as it relates to hypertension was not addressed
• Male gender (AHR 1.88, 95% CI 1.49–2.39), increasing age (AHR 1.36, 95% CI 1.02–1.82 for those > 40 years compared to those aged 30 years or less), nadir CD4 count (AHR 0.77, 95% CI 0.60–0.99 and AHR 0.64 95%CI 0.41–1.00 for a nadir CD4 cell count 100–350 and > 350 cells/mm3 compared to < 100 cell/mm3, respectively), and high baseline body mass index (AHR 2.50, 95% CI 1.56–4.01 for those with a BMI ≥ 30 kg/m2 versus normal BMI) were independently associated with increased risk of hypertension
• Neither use of TDF versus AZT, nor use of NVP versus EFV was associated with risk of hypertension in the multivariate model
• Inverse relationships between hypertension risk and CD4 count nadir. Data suggest that immunosuppression and/or viral burden play a role in promoting early vascular damage as evidenced by the association of a low CD4 cell count with subclinical atherosclerotic damage, a processor of hypertension
• Results are the first to document high rates incident hypertension during longitudinal follow-up among initially normotensive PLHIV initiating ART
• Particularly notable was the magnitude of hypertension incidence in younger groups
• Potential mechanisms for increased incidence of hypertension postulated in this paper include HIV-associated chronic inflammation, immune suppression, endothelial activation, and dysfunction, as well as the direct infection of arterial vascular smooth muscle cells by HIV
• Alternatively, incident hypertension in this setting may reflect a “return to health” as individuals gain weight during ART, particularly with advanced pre-ART disease stages
Limitation: smoking status and laboratory results of blood glucose, serum creatinine, serum electrolytes, and serum lipids were not available for most patients; therefore, the contribution of clinical factors known to be associated with hypertension such as diabetes mellitus, chronic kidney disease, and hyperlipidemia could not be assessed
• Prevalence of hypertension was 20.9% (418/1996) rising from 16.9% in 2009 to 32.3% in 2013
• Patients > 50 years of age had 3.12 times the odds of hypertension compared with patients aged 20–29 years (95% CI 2.00 to 4.85)
• Men had 1.65 times the odds of hypertension compared with women (95% CI 1.34 to 2.03) and patients with a BMI of 35–39 kg/m2 had 3.93 times the odds of hypertension compared with patients with a BMI < 25 kg/m2
• Patients with a WHO disease staging of 3 or 4 had 0.60 times the odds of hypertension compared with patients with stage 1 or 2 (95% CI 0.46 to 0.76)
Analysis did not distinguish ART and ART-naive patients as this can confound results
HIV+ on ART, ART naive and HIV-negative participants
• SBP in HIV+ ART was higher (124.9 ± 20.7 mmHg) compared to HIV+ ART naive which was higher than (121.5 ± 20.7) HIV negative (114.8 ± 11.7 p = 0.001)
• hsCRP = 2.9 (1.4–11.6), p = 0.002 were higher among the HIV-naive subjects
• Higher prevalences of the risk factors were noted among the HIV-treated subjects except low HDL-C (p < 0.001) and hsCRP (p = 0.03) which were higher in the HIV-naive group
Immune mechanism or inflammation as it relates to hypertension was not addressed; however, hsCRP was higher among ART-naive patients
• Prevalence was 23.7% (95%-confidence interval 21.1–26.6; rural 21.0% vs. urban 26.5%; p = 0.047)
• Hypertension diagnosis was associated with increasing age, higher body mass index, presence of proteinuria, being on regimen zidovudine/lamivudine/nevirapine and inversely with World Health Organization clinical stage at ART initiation
Immune mechanism or inflammation as it relates to hypertension was not addressed
In this propensity score-matched sample, the estimated average treatment effects on the treated (ATT) for the effects of antiretroviral therapy on systolic (7.85 mmHg, 95% CI 3.72 to 15.68) and diastolic blood pressure (7.45 mmHg, 95% CI 4.99 to 13.61) were statistically significant (p < 0.001 for each)
There is a high probability that the epidemiological association between antiretroviral therapy and increased blood pressure be causal in nature among people living with HIV in Sub-Saharan African settings
Prospective study conducted in Lusaka, Zambia among PLWH
896 cohort HIV+ on ART participants
• 98 (10.9%) had HBP, and 57 (6.4%) had HTN
• Increasing age (10-year increase in age: adjusted odds ratio [AOR] = 1.50; 95% confidence interval [CI] 1.20–1.93), male sex (AOR = 2.33, 95% CI 1.43–3.80), and overweight/obesity (AOR = 4.07; 95% CI 1.94–8.53) were associated with HBP
• Among 66 patients with HBP, 35 (53.0%) reported awareness of the condition
• Pre-ART CD4+ count was not associated with HBP
HBP tends to become more common after ART initiation and may cause HTN
Coinfection with HBV,
HBP was defined as a single elevated measurement, and BP was measured only once at each time point. This may have inflated the number of patients truly needing treatment, as only 58% of patients with HBP were confirmed to have HTN
These data demonstrate that although integration of BP screening and management in HIV care settings was feasible in Zambia, virtually no patient had optimal management of HBP
• The prevalence of HTN was 19.5% among HIV-infected persons
• The prevalence of pre-HTN in HIV-positive and HIV-negative participants was 34.5% and 38.9%, respectively
• The higher prevalence of HTN in HIV patients has been shown to be associated with the use of ART
• In our study, the risk factors that were associated with HTN in HIV-infected patients and the HIV-N controls were older age, increased weight and BMI, and presence of obesity. Male sex was associated with HTN in the HIV-infected population, but this was, however, not so in the general population
• Male sex and duration of exposure to ART and CD4 count levels > 200 cells/mm3 were associated with HTN in HIV-infected patients, whereas the absence of family history of HTN was significantly associated with HTN in both groups
• The mean age, weight, and BMI were significantly higher in HIV patients with HTN as compared to those without HTN, p < 0.05
• A proportion of HIV patients with a family history of HTN and obesity had HTN, and these were statistically significant (p < 0.05)
• Also, the mean waist-hip ratio, duration of illness, exposure to ART, and CD4 count levels were higher in HIV patients with HTN as compared to those without HTN, but these were not statistically significant
Diet and sodium intake of the participants and renal function of the participants which have been shown in several studies to have effect on BP were not looked at in our study
Immune mechanism or inflammation as it relates to hypertension was not addressed
• 80 (9.6%) of them developed hypertension during a median follow-up of 144 days from time of enrolment into the cohort [incidence rate 120.0 cases/1000 person-years, 95% confidence interval (CI) 97.2 ± 150.0]
Traditional cardiovascular risk factors predicted incident hypertension, but no association was observed with immunological or ART status. These data support the implementation of routine hypertension screening and integrated management into HIV programs in rural Sub-Saharan Africa
• Prevalence of hypertension at enrolment was 19.3% (95% CI 17.6–20.9%)
• Age (p < 0.001), male sex (p = 0.004), and body mass index (BMI) (p < 0.001) were independent risk factors for hypertension
• 12 months after initiating ART, a further 31% (95% CI 17.6–20.9%) had developed hypertension. Total prevalence at that point was 50.2%
• Hypertension among those on ART was associated with age (p = 0.009) and BMI (p = 0.008), but not with sex
• There were no independently significant associations between hypertension and CD4+ counts, viral load, or type of ART
Hypertension is common in HIV-infected individuals attending the HIV clinic. Patients initiating ART have a high risk of developing hypertension in the first year of ART
Case control study from Zimbabwe among HIV+ on ART
300 (152 controlled HTN, 152 uncontrolled HTN)
• Adding salt to dishes regularly AOR = 5.69 (3.19–10.16), body mass index (BMI) above 25 kg/m2 AOR = 2.81 (1.60–4.91) and history of elevated blood pressure in previous year AOR = 2.34 (1.33–4.13) were independent risk factors for uncontrolled hypertension
• Independent protective factors were duration more than 2 years since HIV diagnosis AOR = 0.58 (0.35–0.95), duration less than 5 years since hypertension diagnosis aOR = 0.50 (0.30–0.83) and walking or cycling as a means of transport AOR = 0.27 (0.16–0.48)
Salt HTN interaction attributed to water retention resulting in high intravascular volumes. Immune mechanism or inflammation as it relates to hypertension was not addressed
The prevalence of hypertension was found to be 23.2%
Hypertension is a highly prevalent comorbidity in HIV patients. The risk factors include prolonged use of ART as well as increased body mass index. The effects of hypertension on HIV progression include low CD4+ T cell counts which complicate the underlying immunosuppression
577 HIV-infected and 538 matched HIV-uninfected participants
• HIV infection was associated with 3.3 mmHg lower systolic BP (1.2–5.3 mmHg), 1.5 mmHg lower diastolic BP (0.2–2.9 mmHg), 0.3 m/s lower pulse wave velocity (0.1–0.4 mmHg), and 30% lower odds of hypertension (10%–50%)
• Body mass index mediated 25% of the association between HIV and systolic BP
HIV infection was inversely associated with systolic BP, diastolic BP, and pulse wave velocity
Immune mechanism or inflammation as it relates to hypertension was not addressed
379 HIV-infected patients on ART and 356 controls participated
• Among HIV patients, the prevalence of hypertension was 19.5% (95% CI 15.6–23.6), of which 60.3% (n = 44) was previously undiagnosed
• Among controls, 25.8% (95% CI 21.6–30.7) prevalence of HTN and 37.0% of controls with elevated blood pressure
Immune mechanism or inflammation as it relates to hypertension was not addressed
DBP, diastolic blood pressure; SBP, systolic blood pressure; PLWH, people living with HIV; HTN, hypertension; HIV, human immunodeficiency virus; BP, blood pressure; ART, antiretroviral therapy; PI, protease inhibitors; BMI, body mass index; CI, confidence interval; cART, combinational ART; TDF, Tenofovir; AZT, Zidovudine; NVP, Nevirapine; EFV, Efavirenz; HAART, highly active antiretroviral therapy; LPV/r, lopinavir/ritonavir; TC, total cholesterol; HDL-c, high-density lipoprotein cholesterol
ART Treatment in PLWH Is Associated with Higher Inflammation
As shown in Table 4, we found that PLWH on ART had higher inflammatory markers including IL-6, CRP, intracellular adhesion molecule 1 (ICAM-1), and vascular adhesion molecule 1 (VCAM-1) compared with HIV-negative individuals (Fourie et al.) [55]. Intermediate monocytes (CD14+16+) increased with viremia in immune-compromised patients and microbial translocation was a major force driving chronic systemic inflammation in HIV-positive individuals on ART.
• Biomarkers of increased microbial translocation (lipopolysaccharide binding protein, endotoxin core IgG and IgM, and soluble CD14) were associated with high levels of systemic inflammation before and after initiation of ART, suggesting that impaired gut immune defenses contribute to innate immune activation in this population
All the HIV-infected adults in the study were undernourished
• Persistent immune activation (sCD14 level and kynurenine-tryptophan ratio) and inflammation (IL-6) despite ART-mediated viral suppression predicted future atherosclerotic burden among HIV-infected Ugandans
Immune mechanism or inflammation as it relates to hypertension was not addressed
PLWH, people living with HIV; HIV, human immunodeficiency virus; CRP, C-reactive protein; ART, antiretroviral therapy; IL, interleukin; TNFα, tumor necrosis factor alpha; cART, combinational ART; sCD14, soluble CD14; sCD163, soluble CD163; VCAM-1, vascular cell adhesion molecule 1; ICAM-1, intercellular adhesion molecule 1
Discussion
In the current study, we found that the prevalence of hypertension in PLWH in Sub-Saharan African countries ranged from 2.0 to 50.2% with most cases among those receiving ART. Besides traditional risk factors and the effect of ART on blood pressure, IL-17A, IFN-γ, and CD4+ T cells were among the inflammatory parameters associated with hypertension in ART treated PLWH [13••, 56]. The mechanism of interaction between immune activation or inflammation and hypertension in HIV remains elusive and warrants further studies. Our findings and conceptual hypothesis of how immune activation may contribute to hypertension in HIV is shown in Fig. 1. We propose that HIV viral protein and ART interacts with components of the immune system to synergistically induce kidney damage, vascular dysfunction, alterations in sympathetic nervous outflow and lead to hypertension. This process is exacerbated by presence of traditional risk factors exacerbates including obesity, excess dietary salt intake, smoking, and genetic predisposition.
Fig. 1
Conceptual schematic of the effect of HIV infection and treatment can activate the immune system leading to hypertension. Viral proteins and/or antiretroviral therapy (ART) activates antigen presenting and T cells which infiltrate the vasculature and the kidneys and release cytokines IL-6, IL-17A, and IFN-γ which promote vascular dysfunction, retention of sodium, and water, leading to hypertension
×
Anzeige
Prevalence of Hypertension in HIV
The prevalence of hypertension in PLWH varies by population and subgroups even within the same countries. Similar to our findings, Martin-Iguacel et al. and Nguyen et al. reported prevalence ranging from 4 to 54% [57••] and 8.7 to 45.9% among PLWH in low- and middle-income countries [58]. However, in our study, we further segregated prevalence by HIV infection and ART treatment and report magnitude of differences between the groups (Table 1). Higher hypertension prevalence was reported in ART treated PLWH compared with ART-naive participants except in the study by Ogunmola et al. who reported the opposite [22]. This contradictory finding is likely due to differential effects of specific ART regimens and other traditional risk factors differing between study populations. The effect of specific regimens on blood pressure has not yet been well established except for the low to moderate increase attributed to non-nucleoside reverse transcriptase inhibitors (NNRTI’s) and protease inhibitors (PIs) [59, 60]. Prior studies have shown that patients become hypertensive in most cases at least after 2 years of ART and systolic pressure increases further after 5 years of ART [60], and that there is no association between HIV status, ART, and hypertension following short-term follow-up of less than 2 years [22, 61].
Markers of Immune Activation or Inflammation Associated with Hypertension in HIV
Traditional risk factors associated with hypertension in HIV such as older age, male gender, African-American, higher BMI, central obesity, previous CV events, chronic kidney disease, family history of hypertension and CVD, diabetes, and dyslipidemia have been well studied [57••, 58]. It is also well established that HIV infection and exposure to ART (more than 2 years), through metabolic disturbances and endothelial dysfunction, might have an additional role in the development of hypertension in HIV patients [57••, 58]. However, little is known about the contribution of the innate and adaptive immune system in the development or propagation of hypertension in HIV.
In our systematic review, we found that an improved immune status as determined by higher CD4 T cells was associated with higher hypertension prevalence [17]. However, one study be Okello et al. found that CD4 T cell count of less than 100 was associated with incident hypertension [61]. Martin-Iguacel et al. and Nguyen et al. also reported similar findings [57••, 58]. We found that T cell-derived cytokines IL-17A and IFN-γ were associated with hypertension in ART treated PLWH as reported by Chepchirchir et al. [13••]. These cytokines have been reported to contribute to the genesis of hypertension in the HIV-negative general population and experimental animal studies [6]. Further studies are needed to ascertain the contribution of CD4 T cells and their cytokines IL-17 and IFN-γ in concert with existing traditional risk factors on blood pressure elevation in HIV.
Immune Activation, Inflammation, and Hypertension
The role of innate and adaptive immunity including specific cell types and cytokines in the development and maintenance of hypertension has been extensively studied in humans and animal models elsewhere [6, 7, 62•, 63‐65]. Using multiple experimental animal models, studies have shown that hypertensive stimuli including angiotensin II, aldosterone, endothelin-1, and salt induce activation of immune cells, which infiltrate the vasculature and the kidneys, and release cytokines that induce increased salt and water retention leading to hypertension [6]. This process is mediated in part by increases oxidative stress leading to oxidation of fatty acids and formation of isolevuglandins (IsoLGs) in antigen-presenting cells. IsoLGs activate these cells to produce pro-inflammatory cytokines IL-6, IL-1β, and IL-23, express costimulatory proteins CD80 and CD86, and activate T cells to produce pro-hypertensive cytokines IFN-γ and IL-17A [7]. In humans, plasma isoprostanes, which are produced in concert with IsoLGs, are elevated in hypertension and markedly elevated in patients with resistant hypertension, and IsoLGs are markedly elevated in circulating monocytes of hypertensive patients [7]. IL-17A and IFN-γ have been implicated in the genesis and maintenance of hypertension due in part to their direct effect in causing endothelial dysfunction and renal damage [6, 66]. Thus, similar immuno-pathophysiological mechanisms underlying hypertension in the general population may also contribute to elevated blood pressure in PLWH.
Anzeige
Potential Mechanisms Leading to Inflammation in HIV
The pathophysiology of HIV-related hypertension seems to emerge from three factors: HIV-related inflammation, HIV-related proteins, and genetic predisposition [59]. It is believed that the HIV viral proteins (negative factor (Nef), transcription proteins (Tat) and glycoprotein 120 (gp-120)) induce hypertension through vascular oxidative stress, smooth myocyte proliferation and migration, and endothelial dysfunction especially in patients with high HIV viral load [59]. Tat, a transactivator protein for HIV replication, is known to be secreted extracellularly by infected cells and has been shown to activate endothelial cells by increasing expression of endothelial-leukocyte adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin which induce initial binding of leukocytes to the blood vessel wall [67]. The levels of soluble ICAM-1 concentration correlate with HIV disease as well as reduction in CD4 count. Tat also induces IL-6 production which increases endothelial permeability [67]. Tat can also suppress the bone morphogenic protein receptor 2 (BMPR-2) responsible for regulating endothelial cell proliferation and survival. This results in increased vascular smooth muscle proliferation and activation of endothelial cells leading to pulmonary arterial hypertension (PAH) [68]. In HIV-positive patients, Tat has been shown to increase the transcription of IL-17 and secretion by T cells causing a pro-inflammatory milieu and has been associated with a devastating immune reconstitution inflammatory syndrome (IRIS) in the brain [69]. The HIV Gp120 is found on the surface of the HIV envelope and can also be found in circulation from viral turn over [70]. Gp120 stimulates monocytes and macrophages to release pro-inflammatory cytokines, promotes an increase in markers of apoptosis, and stimulates the secretion of endothelin-1, a potent vasoconstrictor [68]. It induces endothelial apoptosis by interacting with CXCR4 also expressed on endothelial cells [70]. Gp120 and TNF-α synergistically decrease eNOS and NO in human coronary artery endothelial cells [70].
DCs, the most potent antigen-presenting cells of the innate immune system, have been shown to interact with components of HIV-1 both intrinsically (following fusion of cellular and viral membrane) and extrinsically (prior to being infected) through pathogen recognition receptors (PRRs) resulting in activation of the adaptive immune system [71]. Through their CD28/B7 ligands CD80 and CD86 (also expressed on monocytes and B cells), DCs provide a costimulatory signal necessary for T cell activation and survival. In hypertension, there is an increase in B7 ligand expression leading to T cell activation [5, 72]. An important element in the activation of T cells by DCs and other cells in hypertension is antigen presentation. It is unclear what antigens are presented to T cells in HIV and it is not known if IsoLG-adducted peptides might play a role in hypertension associated with HIV.
Monocyte activation has an important role in HIV-infected persons on ART. Monocytes are chronically activated during HIV infection and it is now evident that inflammatory mediators produced by monocytes (especially IL-6), independent of T cell activation, also predict serious non-AIDS events (SNAEs) in virologically suppressed HIV-infected persons treated with ART [73]. IL-6 production was higher in monocytes than other cells and was associated with increased odds of SNAE and mortality but not the percentage of activated CD4 and CD8 T cells (those expressing CD38 or CD38 and HLA-DR) [73]. Infected monocytes, especially intermediate monocytes expressing CD14+ and CD16+, produce more pro-inflammatory cytokines as compared to their counterpart. They adhere to endothelial cells and transmigrate into the sub endothelial area where their pro-inflammatory activity is increased. It is evident that in HIV, monocytes and macrophages have a reduced phagocytic activity and they age prematurely [70]. Monocytes/macrophages have been implicated in the pathogenesis of hypertension in the general population and experimental animal models [5].
Several mechanisms of immune cell activation have been reported in HIV. First, there is direct binding of the HIV envelope protein gp120/160 to CD4 and/or C-C chemokine receptor type 5 (CCR5) which down-modulates the expression of CD3+ T cell receptor in infected cells resulting in cell death; second, there is an interaction between HIV viral particles and plasmacytoid dendritic cells (DCs) through Toll like receptor (TLR) stimulation which activates CD8+ cytotoxic cells; third, there is microbial translocation from a leaky gut into the circulation leading to a generalized systemic inflammatory process [74]. Also important is the dysfunction of T regulatory cells and immune-senescence resulting in an uncontrolled over activation of immune cells in HIV [74]. The resultant low-grade chronic inflammation which persists even after initiation of ART is associated with hypertension and cardiovascular disease [75, 76].
Anzeige
IL-6 production by monocytes and macrophages is increased following HIV infection and is a valuable prognostic marker for disease progression [77, 78]. Soluble CD14 (sCD14) produced from monocytes and macrophages is also elevated in HIV-infected persons regardless of treatment status and is an independent predictor of mortality [73]. Anzinger et al. reported that increased microbial translocation from the gut resulting from depletion of CD4+ T cells in acute HIV infection results in monocyte activation and higher sCD14 [73]. The expression of programmed death-1 (PD-1), a member of the B7:28 inhibitory molecules, is rapidly increased on CD4+ and CD8+ T cells, B cells, natural killer cells, and monocytes as they interact with PD-L1, its ligand on antigen-presenting cells such that engagement on virus-infected cells leads to impaired generation of effector T cell responses [74]. Other markers which have been associated with immune activation in HIV include increased expression of CD28−, CD57+ and reduced expression of CD127 on CD4+ and CD8+ T cells [79, 80].
In our analysis, we found HIV infection alone is associated with an inflammatory milieu involving higher levels of IL-6, CRP, VCAM-1 ICAM-1, and intermediate monocytes (CD14+16+) among studies conducted in Sub-Saharan African cohorts [17, 55]. There is a generalized systemic immune activation following HIV infection which subsides but still persists at low-grade or subclinical following initiation of ART involving activation of both CD4+ and CD8+ T cells expressing high levels of CD38 [74]. Other T cell activation markers such as human leukocyte antigen–antigen D related (HLA-DR) as well as increases in pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1 beta (IL-1β) have been reported in PLWH in the western countries [74]. Increased expression of CD38 alone or in concert with HLA-DR+ in T cells is a marker of disease progression and mortality in some cases correlating directly with HIV viral load and indirectly with CD4+ count [74]. This continuous immune activation and inflammation has been proposed to contribute to endothelial dysfunction, hypertension, and cardiovascular disease [81].
Limitations, Conclusion, and Future Perspectives
Almost all studies except one [13••] were not designed to compare blood pressure or hypertension and inflammation in PLWH as the primary outcomes. There is need for additional prospective and mechanistic studies to establish the relationship between inflammation and hypertension in HIV infection, and ART. Most studies addressing the mechanistic role of inflammation in the genesis and progression of hypertension have been conducted in murine models and humans in the HIV-negative context. The inflammatory milieu in HIV infection is obviously complex and very different from the general population and further studies are needed to determine the specific contribution of the various attributes in HIV including the viral proteins and ART on inducing inflammation associated with hypertension.
Acknowledgments
Graphics were produced using the online ePath3D toll (Protein Lounge, Inc.).
Compliance with Ethical Standards
Conflict of Interest
The authors declare no conflicts of interest relevant to this manuscript.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Mit e.Med Innere Medizin erhalten Sie Zugang zu CME-Fortbildungen des Fachgebietes Innere Medizin, den Premium-Inhalten der internistischen Fachzeitschriften, inklusive einer gedruckten internistischen Zeitschrift Ihrer Wahl.
Mit e.Med Allgemeinmedizin erhalten Sie Zugang zu allen CME-Fortbildungen und Premium-Inhalten der allgemeinmedizinischen Zeitschriften, inklusive einer gedruckten Allgemeinmedizin-Zeitschrift Ihrer Wahl.
Fast ein Viertel der Personen mit mäßig dysplastischen Stimmlippenläsionen entwickelt einen Kehlkopftumor. Solche Personen benötigen daher eine besonders enge ärztliche Überwachung.
Bei Menschen mit Typ-2-Diabetes sind die Chancen, einen Myokardinfarkt zu überleben, in den letzten 15 Jahren deutlich gestiegen – nicht jedoch bei Betroffenen mit Typ 1.
Ob Patienten und Patientinnen mit neu diagnostiziertem Blasenkrebs ein Jahr später Bedauern über die Therapieentscheidung empfinden, wird einer Studie aus England zufolge von der Radikalität und dem Erfolg des Eingriffs beeinflusst.
„Kalte“ Tumoren werden heiß – CD28-kostimulatorische Antikörper sollen dies ermöglichen. Am besten könnten diese in Kombination mit BiTEs und Checkpointhemmern wirken. Erste klinische Studien laufen bereits.
Update Innere Medizin
Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.
