Effects of physical exercises on inflammatory biomarkers and cardiopulmonary function in patients living with HIV: a systematic review with meta-analysis

For decades, the Human Immunodeficiency Virus (HIV), which induces cell death (CD4- helper cells) [1], has remained a key public health issue globally [2]. Global epidemiological data suggest that HIV-related deaths are common among women in the reproductive age group (15–49), especially the Sub-Saharan Africa which accounts for 64% of the total new cases of HIV infection [3]. Meanwhile, Nigeria is the second largest HIV-prevalent country in the world, after South Africa [4]. However, the discovery of the Highly Active Antiretroviral therapy (ART) and its advancement has changed the severity of the HIV infection, for which reason it is currently managed as a chronic condition [5], rather than an outright “death sentence.” Thus, ART usage reduces the mortality rate associated with HIV by decreasing the viral load, boosting the immune function, and reducing the threat of AIDS-defining opportunistic illnesses (OIs) [6]. A reduction in opportunistic diseases was possible through a reduction of HIV-related inflammation/immune activation [7], decreased risk of HIV transmission [8], improved CD4 T-cells/immune response and therefore decreased progression to AIDS [9]. All these effects of ART mentioned above account for a remarkable improvement in the life expectancy of the people living with HIV (PLWH) [10]. However, despite the benefits of this drug, PLWH are still associated with lactic acidosis, dyslipidemia & lipodystrophy, neuropsychiatric symptoms, liver toxicity, gastrointestinal intolerance, lipid abnormalities [11], increase creatinine kinase level [12] and cardiopulmonary dysfunction [13]. Some of these conditions exist as a result of an increased inflammatory response associated with HIV [14, 15] which is not fully suppressed by the use of ART [16‐18]. Hence, high levels of Interleukin 18 (IL-18) in the sputum/plasma and plasma-related Interferon gamma (IFN-ϒ), which is associated with high pressures from the pulmonary artery [19], have been reported in PLWH. Therefore, early management of inflammation is essential in tempering HIV/ ART -associated morbidity [20], and can be achieved through improved physical activity level.

Systemic inflammation commonly associated with HIV is linked to many chronic diseases [21]. In fact, increased expression of pro-inflammatory mediators may trigger the release of reactive oxygen species (ROS) and constitutes an important component of molecular and cellular tissue damage mechanisms in a wide range of chronic human diseases [22, 23] that may include cancer and cardiopulmonary conditions. In fact, the C-reactive protein (CRP – an acute phase protein and a biomarker of inflammation) is increasingly considered to be involved In systemic response to inflammation [24], and lies on the path of biological plausibility for cancer induction [25]. Similarly, several studies had observed high levels of systemic fibrinogen and CRP with pulmonary dysfunction [14], especially; chronic obstructive pulmonary disease [26]. For instance, there is evidence of an association between circulating inflammation markers and forced expiratory volume at the first second (FEV₁) [27], though the physiological mechanisms relating low-grade systemic inflammation and pulmonary disease is not fully delineated [28, 29]. However, it is possible that the induced oxidative stress would have involved pro-inflammatory mediators, which should adversely compromise the patency of the airways or damage the lung tissues/cardiac function [30, 31]. Therefore, factors that influence systemic inflammation may play a role in the induction of cardiopulmonary diseases in HIV conditions and should be addressed in prevention efforts. Physical exercise has been reported as having anti-inflammatory effects in intervention and large population studies of non-HIV infected individuals [32, 33], and therefore may attenuate inflammatory response in HIV conditions.

Physical exercise intervention has resulted to a significant increase in cardio-pulmonary fitness [34] and improved quality of life (QoL) [35] mostly linked to improved aerobic capacity, endurance [36] and immune function (i.e. improved CD⁴⁺ cell counts) in PLWH [37]. In addition, a number of studies propose that a lifestyle of physical activity in moderate/high intensities reduces the serum concentration of C-reactive protein (CRP) by 6–35% [38] and improves cardiorespiratory fitness [39]. Invariably, these findings suggest that the profile of serum concentration of CRP and cardiorespiratory fitness may vary proportionately to the level of physical activity. Hence, a physically active lifestyle may not only be expected to improve chronic inflammation, (which have been implicated in the induction of cancer) but likewise cardiorespiratory fitness/function, which should positively influence the quality of life (QoL). This view was corroborated by findings from the Women’s Health Study (WHS) prospective study of 27,055 healthy elderly women, which revealed that physical activity ameliorated the risk of cardiovascular disease (CVD) through its effect on chronic inflammation and other known risk factors [40]. In addition, other studies provided valuable insights into the direct effects of aerobic and resistance exercise training on certain health indices often compromised by HIV infection and ART. For instance, Levinger et al. [41], and Philips et al. [42], indicated that resistance training has positive effects on chronic diseases by reducing the plasma concentrations of pro-inflammatory cytokines. Neto et al. [43], also reported that combined aerobic and resistance exercises are effective in improving muscle strength, energy, VO₂ peak and health status of patients with HIV. Another study by Zanetti et al. [44], demonstrated the efficacy of non-linear resistance training in adjusting the inflammatory profile and anthropometry of PLWH.

So far, the mechanism by which increasing levels of physical activity improve plasma CRP seems to be explained by other factors apart from its effect on body weight, since both low levels of physical activity and high levels of body mass index (BMI) were independently associated with increased serum levels of inflammatory biomarkers [45]. Thus, the exercise-induced release of heat shock protein, immune function alteration or reduced tissue hypoxia, have been highlighted as other possible mechanisms by which increased physical activity may reduce plasma CRP [46]. By itself, physical activity may attenuate systemic inflammation or when combined with relevant changes in body weight or composition [47]. Moreover, there is evidence that physical activity boosts the activity of macrophages, natural killer cells, lymphokine-activated killer cells, neutrophils, and regulating cytokines with net anti-inflammatory and immunomodulation effects, which may contribute to the protective value of physical activity [48]. Based on the available scientific evidence so far cited, it is reasonable to expect that physical exercise will improve or sustain cardiopulmonary/physical fitness and general health and wellness [49], in HIV conditions. Therefore, it is understandable why physical exercise has been proposed as an adjunctive therapy for drug intervention in people with chronic diseases [50].

There is no doubt that the literature is replete with scientific evidence on the positive effects of physical exercises on multisystemic function in PLWH, and is therefore considered suitable as part of their management program [51]. Although, the results of some studies suggest an association between high physical activity level and lower levels of C-reactive protein and other surrogate markers of inflammation, findings from intervention studies of exercise alone or exercise and diet combined have been conflicting [52, 53].. Accordingly, the effects of physical activity on surrogate biomarkers of systemic inflammation, especially CRP, in patients with HIV may still be faced with much debate. Therefore, notwithstanding the positive findings in support of the role of physical exercise modalities in ameliorating symptoms of systemic inflammation, and cardiopulmonary function, a systematic appraisal of the available evidence in the literature is still required to determine the level of evidence, and therefore guide practice and further research. The aim of this systematic review was therefore to determine the impact of physical exercises on cardiopulmonary function and biomarkers of inflammation in HIV patients. The review question is: What are the effects of physical exercises (aerobic exercises or resistance exercises) on cardiopulmonary function and Inflammatory biomarkers in patients living with HIV? To answer the review question, specific review objectives sought to determine the effects of physical exercises on 1) inflammatory biomarkers and 2) cardiopulmonary function in patients living with HIV.

This Systematic review used the International Prospective Register of Systematic Reviews (PROSPERO) criteria and was certified on 21st June 2018 (registration number PROSPERO 2018: CRD42018098667).

Twenty-two trials determining the efficacy of various exercise interventions for improving the level of inflammatory biomarkers and cardiopulmonary functioning in patients living with HIV infection undergoing ART were reviewed. Studies included for the review were mainly of fair methodological quality with a moderate risk of bias. Five studies stated that there exists a significant change in inflammatory cytokines in the exercise (EX) group following the period of the intervention in relation to the control (CON) group while three studies reported no significant effect of the intervention on the biomarkers between the EX and CON group. Evidence from 12 studies reported a statistically significant improvement in the cardiopulmonary related parameters while two other studies reported no significant improvement in the study.

Meta-analyses suggest that performing constant or interval aerobic exercise or a combination of constant aerobic exercise and progressive resistive exercise for at least 15 min, 23 times per week for at least 4 weeks may improve the cardiopulmonary functioning (maximum/peak oxygen consumption) of the individual. Results suggest that physical exercise is safe for medically stable adults living with HIV. This result is supported in that few or no reports of adverse effects of exercise as an intervention among studies as well as the absence of change in CD₄⁺ cell count and viral load in the subjects. It is also based on participants who completed the exercise interventions and for whom there were adequate follow-up data which was clearly stated. Twenty-two studies were incorporated into the update of this systematic review, out of which 14 of them were included in the meta-analyses [36, 44, 60, 61, 65, 67, 69‐74, 76, 80].

For the studies that assessed inflammatory biomarkers: four out of eight [44, 60, 61, 64] studies were included in the meta-analyses conducted for interleukin-6 and interleukin-1β. The meta-analyses revealed that exercises had no significant effects on the plasma level of these inflammatory biomarkers compared to the control. Our finding is different from the findings of a previous study [81] which revealed that negative side effects, such as caused by chronic inflammation, are known to be improved using the routine exercise. Individual studies [59, 80] reported a significant reduction in high sensitivity C-reactive protein, while Roos et al. [63], reported no significant effect on the outcome. Pedro et al. [62], also reported that there was no significant effect on IL-5, 4, 10 that were assessed. Overall, 25% (i.e. two out of eight) of the studies on the effects of exercises on inflammatory biomarkers reported no significant effect.

For the cardiopulmonary outcomes: Ten of the fourteen studies that assessed for VO2 max were included in the meta-analyses [36, 65, 67, 69‐74, 76], which revealed that there are a potentially clinically significant improvements in VO₂ max among the exercisers when compared with the control group. These findings are similar to findings of previous reviews conducted by Jaggers and Hand [81], Nixon et al. [82], O’Brien et al. [83], O’Brien et al. [84], and O’Brien et al. [85]. Individual studies that evaluated other cardiopulmonary outcomes such as the slope/intercept values for heart-Rate workload relationship [68], WRmax [75], and FEV1 [66], reported a significant improvement in the values of the assessed outcomes. Overall, exercise appears to have a beneficial effect on adults living with HIV with cardiopulmonary dysfunction.

This review includes 21 randomized controlled trials and one case-control trial comparing the effect of different exercise interventions to non-exercising control or an alternative intervention. Eight of the included studies used aerobic exercises as intervention while three of the studies employed the use of resistant exercise only. Eleven of the included studies in this review involved concurrent exercise training (combined resistive and aerobic exercise interventions) thus underlining an increasing trend of combined exercise interventions in the literature [36, 59‐62, 68‐70, 73, 76, 77]. The recommended dosage of aerobic exercise recorded to be effective in this review was based on the exercise Frequency, Intensity, Time and Type (FITT) principle: exercise frequency of 3–5 sessions/week; exercise intensity: 45–80% age-predicted maximal heart rate (APMHR),40–65% of VO2max/peak, 40–75% of heart rate (HR), 50–80% of lactic acidosis threshold (LAT) work rate; exercise time: 15–60 min; and exercise type: prolonged endurance exercise involving large muscle groups, such as those used in walking, running, cycling. The resistant exercises involve exercise frequency of 3–5 sessions/week; exercise intensity: 60–80% of one repetitive maximum (1-RM), 2–5 sets of 8–15 reps. Collectively, the results of this review are complementary to other previous review involving either or both of the interventions highlighting the benefits of exercise for people living with HIV.