The effects of aerobic exercises on high sensitivity C-reactive protein and depression in patients living with HIV infection; a systematic review with meta-analysis

Background HIV infection and chronic use of highly active antiretroviral therapy have been associated with increased expression of pro-inammatory biomarkers (e.g. high-sensitivity C-reactive protein) and major affective disorders (e.g. depression). There is a growing research interest in aerobic exercise as an adjunct therapy on inammatory outcomes and depression in people living with HIV (PLHIV) who are undergoing antiretroviral therapy. Synthesizing and appraising available evidence may be essential to guide practice and future research on exercise intervention to this population. This review evaluated the effects of aerobic exercises on serum levels of high-sensitivity C-reactive protein (hs-CRP) and depressive symptoms in PLHIV. Methods Cochrane Central Register of Controlled Trials, MEDLINE, PEDRO, EMBASE, AMED, CINAHL, and Web of Science were systematically searched to include clinical trials that investigated the effects of aerobic exercises on hs-CRP and/or depression in PLWH. Two reviewers independently screened all the articles for eligibility and also evaluated the risk of bias using the Cochrane Collaboration risk of bias assessment tool. Data were extracted and meta-analyses conducted using Review Manager Software. Results Six studies (261 participants) met the inclusion criteria and were included in the review. Four of the studies reported on depressive symptoms and two on hs-CRP outcome The meta-analysis result showed a signicant (Z=3.78, p<0.0002) decrease in depression scores in PLWH; implying that aerobic exercise interventions reduce depressive symptoms among PLWH. The two studies that reported on hs-CRP outcome, found no signicant effect of aerobic exercise on hs-CRP. Overall, the GRADE evidence for this review was of moderate quality. about two ve times per but


Abstract
Background HIV infection and chronic use of highly active antiretroviral therapy have been associated with increased expression of pro-in ammatory biomarkers (e.g. high-sensitivity C-reactive protein) and major affective disorders (e.g. depression). There is a growing research interest in aerobic exercise as an adjunct therapy on in ammatory outcomes and depression in people living with HIV (PLHIV) who are undergoing antiretroviral therapy. Synthesizing and appraising available evidence may be essential to guide practice and future research on exercise intervention to this population. This review evaluated the effects of aerobic exercises on serum levels of high-sensitivity C-reactive protein (hs-CRP) and depressive symptoms in PLHIV. Methods Cochrane Central Register of Controlled Trials, MEDLINE, PEDRO, EMBASE, AMED, CINAHL, and Web of Science were systematically searched to include clinical trials that investigated the effects of aerobic exercises on hs-CRP and/or depression in PLWH. Two reviewers independently screened all the articles for eligibility and also evaluated the risk of bias using the Cochrane Collaboration risk of bias assessment tool. Data were extracted and meta-analyses conducted using Review Manager Software. Results Six studies (261 participants) met the inclusion criteria and were included in the review. Four of the studies reported on depressive symptoms and two on hs-CRP outcome The meta-analysis result showed a signi cant (Z=3.78, p<0.0002) decrease in depression scores in PLWH; implying that aerobic exercise interventions reduce depressive symptoms among PLWH. The two studies that reported on hs-CRP outcome, found no signi cant effect of aerobic exercise on hs-CRP. Overall, the GRADE evidence for this review was of moderate quality. Conclusion There was evidence that aerobic exercises of about 24-60 minutes duration, two to ve times per week can lead to a signi cant improvement in depression level but not hs-CRP in PLWH. However, it should not be concluded as 'no evidence of effect' because the included trials do not have su cient power to detect treatment effects. Thus, further homogenous research with enough "power" is necessary for a conclusive estimate of effects.

Background
The use of highly active antiretroviral therapy (HAART) has to a very large extent reduced the morbidity and mortality of people living with HIV infection [1]. Despite the generally recorded improved health outcome, some studies have strongly associated HAART to speci c side effects which includes elevation of in ammatory markers, for example, high-sensitivity C-reactive protein (hs-CRP) [2,3]. Hs-CRP, a non-speci c in ammatory biomarker, has been noted by both the American Heart Association and Centres for Disease Control as an independent predictor of increased coronary risk; and they recommended that individuals with hs-CRP levels greater than or equal to 3.0 milligrams per liter would likely need more intense management and treatment of heart disease [4].
Several studies have reported signi cant declines in hs-CRP levels following aerobic exercise interventions among older individuals [5], obese women [6] and breast cancer survivors [7]. The third National Health and Nutrition Examination Survey observed that 21% of sedentary individuals had increased hs-CRP levels compared to 13% of moderately active individuals [8]. Yet, a meta-analysis of randomized controlled trial reported a non-signi cant decline in hs-CRP levels among healthy subjects following an aerobic exercise intervention [9]. The existing studies that investigated the effects of aerobic exercise interventions on circulating in ammatory biomarkers have produced inconsistent results, and no meta-analysis of effects have been conducted to explore the intervention effects of aerobic exercises on hs-CRP in PLWH.
Depression is amongst the most common neuropsychiatric disorders that burden individuals with HIV infection [10]. Depression could be as a result of the effects of the infection in the brain, shock after diagnosis, presentation of symptoms, a death of another HIV patient, loss of friends due to HIV infection status, as well as side effects of HAART [11]. Exercise has proven to have a short-term effect on depression among general population [12,13]. However, there is no recent meta-analysis that has evaluated the effects of aerobic exercise on depression in PLWH [14].
This systematic review is therefore aimed at evaluating the effects of aerobic exercises on serum levels of high-sensitivity C-reactive protein (hs-CRP) and depression in PLWH undergoing HAART. Speci cally, two questions guide this review: (a) Are aerobic exercise interventions effective in reducing hs-CRP levels in patients with HIV undergoing HAART? , and (b) Are aerobic exercise interventions effective in reducing depressive symptoms in patients with HIV infection undergoing HAART?

Design
This systematic review and subsequent network of meta-analysis was conducted and reported according to the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) 2015 guideline [15,16].

Search strategy
A search strategy was developed with health-research librarian, and piloted (see Appendices I, II, III, IV) following the guidelines speci ed by the Cochrane Handbook for Systematic Reviews [17], and the guidance for undertaking reviews in health care by the Centre for Reviews and Dissemination [18]. The following databases were searched from inception until September 2018, to include studies that reported the effects of aerobic exercise on hs-CRP level and depression scores: Cochrane Central Register of Controlled Trials, PubMed (MEDLINE), PEDRO, EMBASE, Allied and Complementary Medicine Database (AMED), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science Core collection. The following search terms were adapted for each database: HIV OR seropositive OR HAART OR anti-retroviral therapy, highly active OR anti-HIV agents AND aerobic exercise OR physical activity OR acute exercise OR exercise training OR physical exertion OR sports AND C-reactive protein OR acute-phase proteins OR reactants OR glycoproteins OR blood proteins OR immunoproteins AND depression OR depressive symptoms OR emotional depression OR depressive syndrome OR neurotic depression OR melancholia OR affective disorders OR adjustment disorders. Additionally, the reference lists of the included articles were hand searched. Attempts were made to collect unpublished data, we searched the National Library of Medicine's clinical trial registry, directory of open-access repository websites and conference proceedings. However, there was only two ongoing trials [19,20] still at the recruiting of participants stage that aim to evaluate the effect of aerobic exercise on depression and/or hs-CRP level among PLWH receiving HAART.

Eligibility criteria
The following eligibility criteria were applied in selecting studies.
An article was included in the review if; 1. The study population were adults (≥ 18 years old) with HIV infection receiving HAART.
2. The intervention was aerobic exercise, de ned as physical activity of low to high intensity requiring free oxygen and utilization of oxygen to su ciently meet energy demands during exercise through aerobic metabolism [21]. No particular restriction was considered regarding a particular form of aerobic exercise, dose, frequency, intensity, and duration of intervention or follow up period after intervention. As many such interventions may be complex, including several components, other interventions in addition to aerobic exercise including medications, nutrition, and health education were also included as long as the effect of aerobic exercise intervention could be determined.
3. The primary outcome measure was the hs-CRP level, and/or the secondary outcome was any measures of depression especially generic validated tools (i.e. depression tool not developed for a speci c condition, e.g. Cardiac Depression Scale). Examples of generic depression validated tools include, but not limited to; Centre for Epidemiological Studies-Depression Scale, Montgomery-Asberg Depression Scale, Becks Depression Inventory score, and Positive and Negative Affect Schedule. 4. The control or comparator can be any control including non-exercise or resistance exercise.
5. The setting in which the study was conducted were any of the following: hospital (e.g. inpatient, acute or outpatient), rehabilitation homes, community or long-term care.
. The article was randomized controlled trials (RCTs), and non-RCTs including quasi-RCTs, controlled clinical trials, pre-test post-test clinical trials.
An article was excluded if: 1. The intervention was not aerobic exercise based on the de nition provided above.
2. It was an opinion paper, qualitative studies, narrative reviews, systematic reviews, letter to the editors or commentaries.
3. If the control group was not clearly de ned.
Study record, selection process and data management  (Table 8.5a of the Cochrane Handbook for Systematic Reviews of Interventions) was used to assess the articles in six key domains: 1) selection bias (random sequence generation, allocation concealment); 2) performance bias (blinding of personnel and participants); 3) detection bias (blinding of outcome assessments); 4) bias due to attrition (incomplete outcome data, including dropouts and withdrawals); 5) reporting bias (selective reporting); and 6) other bias (other sources of bias not elsewhere addressed) [17]. Articles were rated as 'high risk' or 'low risk' following a well-described procedure (Table 8.5.d of the Cochrane Handbook for Systematic Reviews of Interventions) [17,23]. Then, summary assessment for each important outcome (across domains) within and across studies was made (Table 8.7.a of the Cochrane Handbook for Systematic Reviews of Interventions) [17,23]. Again, any disagreement in the decision between reviewers was resolved by discussion and consultation with the third author (O.A.E.).

Data extraction items
Four authors (E.M.A, O.J.A, I.B.N, M.E.K ) used a standardized extraction form to extract the articles' metadata including authors name, country the study was conducted, participants' characteristics, study setting, sampling method, sample size, intervention characteristics (e.g. components of the intervention, who delivered the intervention, the duration of the intervention and follow-up) (where available), attrition rate, aspects of outcome assessed, the outcome measurement, study ndings (e.g. p value, con dence intervals mean and standard deviation), conclusions and funding sources).

Data synthesis and assessment of heterogeneity
To address the review objectives, the quantitative study outcomes were extracted and presented in a proof table. Mean differences were used for the uniform outcomes with 95% of CI. A meta-analysis was conducted to nd pooled effect sizes across the included studies, using a random-effects model depending on the level of heterogeneity of intervention effects. Heterogeneity was assessed using the Cochrane's χ 2 test (10% signi cance level) and Higgins I 2 for which values of 25%, 50%, and 75% shows low, medium and high heterogeneity respectively as speci ed by the guidance in the Cochrane Handbook for Systemic Reviews of Interventions [17].

Data analysis
Studies were narratively described, and meta-analysis were conducted using random-effects model to evaluate the overall effect of aerobic exercise interventions on depression in patients living with HIV infection [17]. Metaanalysis was possible because of the homogenous nature of study design, intervention, comparator(s) and outcomes of the included studies. A substantial heterogeneity was observed in the two studies that considered hs-CRP as an outcome, therefore, only a narrative synthesis was conducted.
Quality of evidence and strength of recommendation.
Two authors (E.M.A, I.B.N) independently graded the quality of the evidence of the included studies on consistency, design, directness, precision, publication bias and study limitations of the Grading of Recommendations Assessment Development and Evaluation (GRADE) [24]. The included studies were graded as high risk of bias or low risk of bias with evidence statement graded from 'High Quality' to 'Very Low Quality' according to the criteria (Appendix V)

Study inclusion
From the database searches, 429 citations were retrieved. After duplicate were removed, 333 underwent title and abstract screening, of which 321 were excluded. The remaining 12 studies underwent full text screening, and 6 studies providing data on 287 participants were included in the nal analysis ( Figure 1).

Characteristics of Included Studies
Study design and participants Four of the included studies were randomized controlled trials (RCTs) [25,26,27,28]. Two studies design were pre-post, with the participants in a control group receiving strengthening exercise [29], or different levels of aerobic exercises including low, moderate and high intensity of aerobic exercises [30]. The number of participants in each study ranged from 21 [30] and 84 [28] of adults (≥18 years) diagnosed with HIV infection (See Table 1).

Quality appraisal and risk of bias assessment
Results of the quality assessment and risk of bias of the 6 included studies are presented in table 2, and 2 studies were rated as high quality [25,28], while the remaining 4 were rated as low quality [29,26,27,30].

Outcomes reported in included studies
Two studies [28,29] reported high-sensitivity CRP, and four studies reported depression [25,26,27,30]. groups were similar at baseline for all studies included (see Table 3).

Aerobic exercise interventions
The included studies had a wide variation in the types of aerobic exercise intervention used ( Table 2). All the included studies reported all the intervention parameters, FITT-frequency, intensity, time, type of aerobic exercise and duration [31]. Walking was the most common type of aerobic exercise used as an intervention in the included studies [27,28,29,30]. Other type of aerobic exercise used as an intervention was stationary bicycle ergometer [25,26].

Effects of intervention
Except where otherwise stated, the effects of an intervention are reported as comparison of the intervention versus the control group.
High-sensitivity C-reactive protein (hs-CRP) Two studies provided data on hs-CRP [28,29]. One high-quality trial [28] reported no statistically signi cant difference in mean hs-CRP between groups. Also, a low-quality trial [29] reported no statistically signi cant difference in mean hs-CRP between groups (Table 3).

Depression
Four studies [25,26,27,30] reported outcomes on depression. One high-quality RCT [25], reported a signi cant improvement (BDI; p=0.001) in the study group. One other low-quality RCT [27], reported a signi cant improvement (CES-D; p=0.028) in the study group as compared to controls. One low quality clinical trial [30], reported no signi cant (p>0.05) changes of the Montgomery-Asberg depression scores groups. One study [26] that reported outcome on negative mood/depression demonstrated signi cantly lower negative mood in the study group than the control group (Table 3).

Meta-analyses-Effect of interventions
Four studies were included in the meta-analysis. A meta-analysis was conducted to evaluate the overall effect of aerobic exercise interventions on depression (4 studies) in patients living with HIV infection.

Heterogeneity test
There was no signi cant heterogeneity (p>0.1) in the meta-analyses of the effects of the intervention on depression outcome. Therefore, a random effects model was used for the meta-analysis. However, a substantial heterogeneity (p<0.1) was observed in the meta-analyses of the effects of the intervention on hs-CRP. This could be as a result of variations in sample sizes and duration of the intervention. Therefore, only a narrative synthesis was reported.

Results of Meta-analyses
When the four studies [25,26,27,30] that considered depression as an outcome measure were pooled together, there was an overall statistically signi cant (Z=3.78, p<0.0002) change in depression level between the comparison groups. There was a signi cant trend towards a decrease in the depression scores in subjects in the aerobic exercise (intervention) group as compared with the control group ( Figure 2).

Discussion
Six trials evaluating a range of aerobic exercise interventions targeted at improving hs-CRP levels and depression in PLWH undergoing HAART were included in this systematic review. The included studies were generally of fair methodological quality. The major sources of risks of bias were lack of blinding of outcome assessment, participant and personnel, lack of allocation concealment and attrition bias. The two studies [28,29] that evaluated the effect of aerobic exercise on hs-CRP level in PLWH reported no signi cant effect. Evidence from three studies [25,26,27] reported a statistically signi cant decline in the depression scores of the study group as compared to control group. However, a study [30] reported no signi cant change in depression scores between the groups because participants in each group was subjected to different intensity of aerobic exercises, ranging from low to high.
The meta-analyses revealed that aerobic exercise interventions had a signi cant effect on depression scores, causing a decline in the depression scores of the subjects in the intervention group as compared to those in the control group. This evidence is similar to the ndings of a current review [32] that investigated the various pharmacological and non-pharmacological interventions that are effective in the management of depressive symptoms in PLWH. The study included only one article on the effect of aerobic exercise interventions and concluded that exercise could be a remedy to depressive symptoms in PLWH undergoing HAART [32].
For the pro-in ammatory outcome (hs-CRP), a narrative synthesis was conducted due to substantial heterogeneity in the two studies [28,29]. The two studies reported a non-signi cant effect of aerobic exercise intervention on hs-CRP in PLWH. This is in agreement with a meta-analyses of ve articles that reported a nonsigni cant effect of aerobic exercise on hs-CRP among healthy adults [9]. Also, this is similar to a recent systematic review that reported a no signi cant change in biomarkers of in ammation (IL-6 and IL-1β) after exercise intervention [33]. However, the results of the narrative synthesis on effects of aerobic exercise on hs-CRP in PLWH should not be concluded as 'no evidence of effect', because the two clinical trials included do not have su cient power to detect treatment effects. Therefore, more homogenous studies investigating the effect of aerobic exercise intervention on hs-CRP in PLWH are necessary for an effective estimate of effects.
The meta-analysis of the four article (one high quality and three low quality) reported a signi cant effect of aerobic exercise on depression in PWLH undergoing HAART. The evidence suggests that aerobic exercise intervention could be effective in reducing depression; however, because of the low quality of the included articles, we suggest that exercise could be incorporated as an adjunct therapy in the care of PLWH. The recommended dosage of aerobic exercise that could elicit an intervention effect as recorded in this review considering the Frequency, Intensity, Time and Type (FITT) principle is thus; exercise frequency of 3-5 sessions/week; Intensity: 55-75% of age-predicted maximal heart rate, 60-80% of VO 2 max, 50-80% of heart rate reserve (HR); Time: 24-60 minutes and Type: continuous or interval aerobic exercises involving large muscle groups. Such exercises could include, walking, cycling with bicycle ergometer, running, treadmill exercise. It is suggested that quali ed professionals (e.g. physiotherapist) should administer and monitor the exercise programs. Generally, the results of this review is an addition to the existing body of evidence highlighting the bene ts of exercises for PLWH undergoing HAART.

Quality of evidence
Following the speci cations in the GRADE ratings for quality of evidence [24], the evidence could be rated as a moderate quality evidence. This is as a result of the identi cation of speci c bias in the included studies. Some studies included in the review demonstrated a high risk of selection bias due to non-utilization of random sequence generation in the recruiting of participants. Some other included studies had detection bias because the assessors were not blinded. Furthermore, some studies had attrition bias due to incomplete outcome reporting and drop-out rate with the failure to conduct an intention-to-treat analysis. Only two out of the six included clinical trials were appraised as high quality, while the others were appraised as low-quality trials. All these culminated to the moderate-GRADE quality of evidence.

Conclusions Implications to Practice
Incorporating aerobic exercise interventions in the care of PLWH could elicit a decline in depression outcomes in this population. Therefore, PLWH could bene t from patient-speci c structured exercise interventions administered by physiotherapists as part of the multidisciplinary health care strategies. However, caution should be applied in using this exercise prescribed above because of the low quality of the studies included that evaluated the effect of aerobic exercise on depression outcomes on PLWH taking HAART. There was no signi cant effect of the aerobic exercise interventions on hs-CRP. However, the interpretation of this evidence should not be seen as 'no evidence of effect' because the individual clinical trials did not attain su cient power to detect treatment effects in this population.

Implications to research
The existing pool of RCTs regarding the effects of aerobic exercise on the speci ed outcomes, especially hs-CRP and depression is insu cient. Among the few articles found, majority of them were of low quality with some methodological issues including small sample size and contains elements of high risk of bias.
Therefore, further studies, adequately powered and would demonstrate low risk of bias including blinding of assessors and participants, use of random sequence generation and allocation concealment are necessary.
This would strengthen the scienti c evidence and inform practice in the management of in ammatory responses and depression in PLWH.

Limitations of the study
While we made considerable effort to ensure the robustness of the search strategy, potentially relevant studies may not have been identi ed if authors did not use the "MESH" terms we used in our search. Also, it is possible that some studies published in other languages may have been missed since we limited our search to only articles published in English. Funnel plot or sensitivity analysis to determine publication bias (false positives) was not performed in the meta-analysis, because only 4 studies were included in the meta-analysis, which is less than Cochrane recommended number of ten or more than ten studies needed to perform funnel plot or sensitivity analysis.