High-sensitivity C-reactive protein among people living with HIV on highly active antiretroviral therapy: a systemic review and meta-analysis

The human immunodeficiency virus (HIV) is a persistent public health problem that currently affects approximately 36.9 million individuals worldwide [1]. This pandemic has grave economic implications, especially in high-prevalence regions such as sub-Saharan Africa (SSA) [2]. Sub-Saharan Africa remains the epicentre for the HIV pandemic, accounting for more than 70% of the global infected population [3]. However, the availability of highly-active antiretroviral therapy (HAART) has been widely acknowledged for its effectiveness in significantly improving life expectancy and quality of life among people living with HIV (PLWH) [4‐6]. Despite these improvements, prolonged use of HAART has been associated with other comorbidities (diabetes mellitus, hypertension, and dyslipidemia) that may lead to the development of cardiovascular diseases (CVDs) [7, 8]. Noteworthy, PLWH on long-term HAART are predicted to be two times more likely to develop CVDs compared to those without this condition [9], whilst the proportion of deaths attributed to CVDs in PLWH on HAART has doubled in the last decade [6, 8]. This knowledge has shifted the focus of care for PLWH, and it now calls for a better understanding of the disease pathophysiology, which makes it necessary to devise new intervention strategies to combat CVD-related complications.

Traditional risk factors and comorbidities such as diabetes mellitus, hypertension, and dyslipidemia are known to be associated with the development and progression of CVDs [10, 11]. These factors are often accompanied by inflammation, a pathological hallmark for HIV infection and CVDs [12]. Although inflammation is necessary for an adequate immune response, a dynamic balance must be achieved between pro- and anti-inflammatory factors in order to suppress infection and minimize any metabolic complications [13, 14]. Beyond their involvement in driving undesired immune activation [15], the most commonly studied pro-inflammatory markers with regard to the pathogenesis of HIV and CVD include interleukin 6 (IL-6), tumor necrosis factor (TNF-α), and high-sensitivity C-reactive protein (hs-CRP). These markers are, in part, associated with the extended use of HAART [16, 17]. Having previously been considered a traditional marker of infection and cardiovascular events [18], hs-CRP is now acknowledged for its role in the underlying inflammatory processes. This includes its activation of other pro-inflammatory cytokines such IL-6 and TNF-α [19].

As such, persistently elevated levels of hs-CRP are deemed to be among the reliable predictors of CVDs in PLWH on HAART [20‐25]. However, other researchers have not seen this effect in PLWH on HAART [26, 27]. Several factors can contribute to the negative association in PLWH, including high lipid profiles, ethnicity, geographical location, and duration of treatment with HAART [24, 26]. Besides updating the status of clinical evidence on the role of this pro-inflammatory marker in PLWH, it remains essential to establish or generate data to evaluate whether hs-CRP levels may be a reliable biomarker to predict CVD risk in PLWH on HAART. Perhaps highlighting the significance of the current systematic review and meta-analysis to assess the levels of hs-CRP in relation to the manifestation of CVDs in PLWH on HAART.

Significantly contributing to the global disease burden, CVD have become a leading cause of morbidity and mortality for PLWH in the era of effective HAART [28]. It has therefore become imperative to understand the pathogenesis of CVD within PLWH, including relevant biomarkers that drive a pro-inflammatory response like hs-CRP [25]. In fact, it has been reported that hs-CRP may be a useful biomarker associated with the development of CVD-related complications in PLWH on HAART [24, 25, 58]. Despite updating the status of clinical evidence on the relevance of hs-CRP levels in PLWH, this review aimed to establish whether this pro-inflammatory marker is modulated independently in those on HAART. Importantly, beyond reporting on the levels of hs-CRP, the current review analyzed evidence on CVD-related outcomes, including lipid profiles to predict CVD risk in PLWH on HAART. To comprehend the potential influence of ethnicity and geographic locations, clinical data was additionally examined based on the world regions classified by the country where it was published. Both the systematic approach and meta-analysis were done to strengthen the reported data.

Twenty-two studies qualified for inclusion in this systematic review, with most studies (n = 11) coming from the African region [27, 34, 36, 38, 43‐48]. The latter was expected since the sub-Saharan African region remains the epicenter of the Human immunodeficiency virus pandemic, with skyrocketing infections [3, 59]. In fact, the sub-Saharan African region is estimated to overtake high-income countries with an increased burden of noncommunicable diseases, particularly due to coronary artery disease and stroke [60, 61]. With increasing research being channeled into understanding the pathogenesis of HIV and associated complications that could be implicated in driving the development of CVD, especially the involvement of inflammation [7, 21]. Consistent with this notion, the qualitative analysis of data presented in this review clearly showed that hs-CRP levels in PLWH on HAART are significantly increased when compared to PLWH not on HAART or those without HIV (Table 1). This evidence was supported by a meta-analysis showing significantly elevated levels of hs-CRP in PLWH on HAART when compared to controls (Figs. 2 and 3). With most studies supporting this increase of hs-CRP in studies from Africa, when compared to both Europe and the United States. Further exploration using subgroup analysis did not indicate any apparent differences in statistical values, suggesting that more studies are required to assess the influence of geographical region on hs-CRP levels in PLWH on HAART. In fact, these findings that support raised levels of hs-CRP in PLWH on HAART were consistent regardless of treatment duration and were not influenced by the type of HAART regimen. This indicates that inflammation is a predominant feature in PLWH regardless of viral suppression. This hypothesis has been increasingly explored recently [21, 42], with more evidence required to understand its potential in causing the development of CVD. The findings from our analysis are consistent with results reported by Avan et al., [24] and De Luca et al., [58], where they also observed an association between the hs-CRP levels and CVD-risk in PLWH on HAART. In addition, in the Strategic Management of Antiretroviral Therapy Study (SMART), it has been shown that hs-CRP levels are associated with CVD events and all-cause mortality risk [23, 62, 63]. It's essential to note that the relationship between HIV, HAART, and inflammation is complex, and response among individuals may vary due to lifestyle and geographic locations. Furthermore, different antiretroviral drugs may have varying effects on inflammation. In cases where individuals on HAART show higher CRP levels compared to those not on HAART, a thorough investigation of factors such as medication adherence and potential concurrent health conditions is essential. Also, consistent monitoring and open discussions with healthcare providers are vital for optimizing HIV management and overall well-being.

Abnormal lipid profiles including raised levels of total cholesterol, LDL-c, and glycerides, to reduced concentrations of HDL-c have become reliable markers to evaluate CVD-risk in pathological settings [27, 64]. This explains routine measurement of lipid profiles in PLWH, including those on HAART [35, 65]. Interestingly, in our systematic review, especially in the data emanating from Africa, there was a strong correlation between elevated hs-CRP levels and abnormal lipid parameters, suggesting a potential increased risk of CVD in PLWH on HAART [27, 35, 45, 46, 50, 65, 66], which occurs regardless of the perceived benefits of treatment. Furthermore, our meta-analysis showed that HDL-c levels were significantly reduced in PLWH on HAART compared to controls (Fig. 4). Whereas the levels of LDL-c, total cholesterol, and triglycerides were significantly elevated in PLWH on HAART compared to controls (Figs. 4 and 5). Thus, the altered blood lipid status, as confirmed by evidence synthesized in this study, shows that PLWH on HAART indeed have an increased risk of developing CVD. This was in accordance with previously reported studies, which indicated that PLWH on HAART have an increased risk of developing CVD [27, 45, 65]. The increased CVD risk may relate to some of the metabolic side effects, such low bone mineral density [67], that are most pronounced in patients treated with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) [27, 35, 45, 46, 50, 68] or protease inhibitors [47]. These findings may have clinical implications if not given enough attention. These may include implications in the development of CVD-related events such as myocardial infarction, heart failure, and peripheral artery disease because elevated levels of hs-CRP are consistent or identified in all these conditions in both PLWH and the uninfected individuals [27, 35, 69]. In addition, while the specificity of hs-CRP may be influenced by extended storage or the presence of EDTA in both serum and plasma [70‐72], we are confident that these factors did not significantly impact the overarching conclusion of the present systematic review. This confidence stems from the fact that most studies included in the review reported on the serum levels of this acute phase protein (73%).

The current systematic review and meta-analysis is not without limitations. Noteworthy, most studies were composed of relatively small sample sizes; thus, the observations made remain to be explored in future studies with larger sample sizes. Another limitation is that most studies were cross-sectional rather than longitudinal, that may provide an advantage of following up on participants. There was also a high level of statistical heterogeneity among included studies. In this study the majority of studies included in the review reported on the serum levels of this acute phase protein (73%) as compared to plasma (27%). Furthermore, not all CVD-related outcomes were reported in the current analysis. However, there are also strengths of this review, which includes it being the first systematic review and meta-analysis that provides a comprehensive overview and meta-analysis of the association between hs-CRP and PLWH on HAART. Further providing much-needed information for evidence-based health care in terms of monitoring and limiting noncommunicable disease-related complications in PLWH on HAART.

The current systematic review and meta-analysis provide evidence that elevated levels of hs-CRP and lipid profiles are prevalent in PLWH on HAART, and this may increase the risk of CVD complications (Fig. 8). These outcomes pose challenges in policy implications on care for PLWH, especially the medical care that involves the long-term use of HAART. Addressing these challenges becomes crucial for policymakers, healthcare providers, and researchers to develop strategies that balance the long-term benefits of HAART for managing HIV with the emerging concerns related to cardiovascular risks. In addition, we motivate for large sample and longitudinal studies to be undertaken to clearly elucidate the influence of HAART use on CRP levels, lipid profiles, average age groups, follow-up duration and duration of HAART treatment and its relationship with the development of CVD in PLWH.