Effectiveness of aerobic exercise for adults living with HIV: systematic review and meta-analysis using the Cochrane Collaboration protocol

We included randomized controlled trials (RCTs) comparing aerobic exercise (or combined aerobic and resistance exercise) with no aerobic exercise or another exercise or treatment modality performed at least three times per week for at least four weeks [13]. We included studies of adults (18 years of age and older) living with HIV at all stages of infection with or without comorbidities. We defined aerobic exercise as a regimen containing aerobic interventions performed at least three times per week for at least four weeks. Aerobic interventions included but were not limited to walking, jogging, cycling, rowing, stair stepping, and swimming. Interventions may or may not have been supervised [13].

We assessed immunological (CD4 count, cells/mm³) and virological (viral load, log10 copies) outcomes. Cardiorespiratory measures included but were not limited to maximal oxygen consumption (VO2max), exercise time, oxygen pulse, maximum heart rate, maximum tidal volume, minute ventilation, lactic acid threshold (LAT), maximum work rate, and rate of perceived exertion. Strength measures included amount of weight able to resist in kilograms (1-repetition maximum) for major muscle groups. Weight and body composition measures included any outcome that contributes to the direct or indirect measurement of muscle, fat, bone or other tissues of the body. These included but were not limited to body weight, body mass index (BMI), lean body mass, girth, percent body fat, cross-sectional muscle area, and waist and hip circumference. Psychological measures included general measures of psychological status and health-related quality of life.

In the update of this systematic review, we searched databases from 2009 to April 2013 including Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, PsycINFO, CINAHL, EMBASE, Web of Science: Science Citation Index, SPORTdiscus, Virology and AIDS Abstracts and LILACS. We also searched clinicaltrials.gov and reference lists from pertinent articles. All languages were included. See Additional file 1 for the detailed MEDLINE search strategy which we modified as needed for use with other databases.

All abstracts retrieved from the search were reviewed independently by two reviewers (KKO and AMT) who applied the following four inclusion criteria to determine if the abstract warranted further investigation: a) Did the study include human participants who were HIV positive? b) Did the study include adults 18 years of age or older? c) Did the study include an aerobic exercise intervention performed at least three times/week, at least 20 min per session for at least four weeks? d) Was there a randomized controlled comparison group?

When the review based on the abstract alone indicated that one or both raters believed the study met eligibility criteria (i.e., if reviewers answered “yes” or “unsure” to the four questions) then full versions of the article were independently reviewed by the two reviewers to determine article inclusion. In instances where there was a lack of agreement by the two reviewers, a third reviewer was asked to review the full article to determine final inclusion.

Data were extracted onto standard data extraction forms independently by at least two reviewers (KKO and AMT and/or SAN). Data extracted included the study citation, study objectives, study design, length of study, time at which participants were assessed, inclusion and exclusion criteria for participants, characteristics of included participants (i.e., age, gender, stage of disease, comorbidity), description of intervention(s) (i.e., frequency, intensity, duration, type, level of supervision, location of intervention), types of outcome variables assessed and their values at baseline and study completion, and number of participants at baseline and study completion (including number of withdrawals). For the purposes of this review, constant exercise was defined as exercise at a constant intensity for a period of time. Interval exercise was defined as exercise conducted at a varied intensity for a total period of time. The reviewers met to achieve consensus regarding any difference in data interpretation or extraction from included studies that arose during the review process. In the case of missing data, authors were contacted in an attempt to obtain further information.

Two authors assessed the risk of bias in the included studies using the Cochrane Collaboration’s tool for assessing risk of bias [14]. Potential biases in studies may have included selection bias (random sequence generation and allocation concealment which may result in systematic differences in the comparison groups), performance bias (blinding of participants and personnel which could lead to systematic differences in the care provided apart from the intervention being evaluated), detection bias (blinding of outcome assessment that may result in systematic differences in outcome assessment), attrition bias (incomplete outcome data), and reporting bias (selective reporting of outcomes) [14].

We assessed the overall quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method [15]. We rated the quality of evidence for each outcome based on categories of very low, low, moderate and high [16]. We downgraded the evidence from high quality by one level for each of the following: attrition bias (where withdrawal rates were >15 %), performance bias (when participants were not blinded to the intervention), detection bias (when assessors of outcomes were not blinded to group allocation), publication bias (when publication bias was suspected), and inconsistency (when moderate I² > 40 % or substantial I² > 75 % heterogeneity exists) [17].

We produced a summary of findings (SoF) table for the main comparison of exercise versus no exercise with the following seven outcomes: immunological (CD4 count) and virological (viral load); cardiorespiratory (VO2max); strength (upper and lower body), weight (body weight); body composition (body mass index); and quality of life (SF-36 sub-scale scores). The SoF table was developed to illustrate the confidence in the effect estimates (quality of evidence) and magnitude of effect for seven key outcomes [18].

Outcomes were analysed as continuous and dichotomous outcomes whenever possible. Meta-analyses were performed using the random-effects model for outcomes using Review Manager (RevMan) computer software whenever there were sufficient data available in the studies, when similar or comparable outcome measures were used, and when participant comparison groups were similar [19].

For continuous outcomes, the weighted mean difference (WMD) and 95 % confidence intervals for the means were calculated whenever possible. For dichotomous outcomes, the odds ratio, absolute difference in odds, relative risk (RR), risk difference (RD), and the number needed to treat (NNT) and 95 % confidence intervals were calculated whenever possible. A p value of less than 0.05 indicated statistical significance for overall effect.

Subgroup analyses were performed whenever possible to estimate whether aerobic exercise interventions were associated with differences among groups using identified outcome measures.

We considered 50 cells/mm³ to indicate a clinically important change in CD4 count, 5 % to indicate a clinically important change in CD4 percentage, and 0.5 log10 copies to indicate a clinically important change in viral load. For cardiorespiratory outcomes, we considered 2 mL/kg/min to indicate a clinically important change in VO2max, 10 beats per minute to indicate a clinically important change in heart rate maximum (HRmax), and 5 min to indicate a clinically important change in exercise time. For strength outcomes we considered 5 kg to indicate a clinically important change in strength for lower extremities, 2 kg to indicate a clinically important change in strength for upper extremities. For weight and body composition outcomes, we considered 3 kg to indicate a clinically important change in body weight (which equals approximately 5 % of the average baseline body weight of participants), 5 cm to indicate a clinically important change in girth (waist and hip circumference), 3 cm to indicate a clinically important change in waist-to-hip ratio, 5 kg/cm² to indicate a clinically important change in body mass index, 5 kg to indicate a clinically important change in fat mass, 5 % to indicate a clinically important change in percent body fat, and 5 cm² to indicate a clinically important change in leg muscle area. For psychological outcomes, we considered 10 points to indicate a clinically important change in the sub scales of the SF-36 quality of life questionnaire; and 5.6 to indicate a clinically important change in the sub scales of the Profile of Mood States (POMS) scale [20]. While no established minimal clinically important difference (MCID) exists for the SF-36 questionnaire specifically with people living with HIV, we drew from other literature with clinically important differences for the SF-36 with other chronic conditions which demonstrates a small change is approximately 10 points [21, 22]. No other established MCID values exist for the other outcomes. Authors based the a priori estimates based on a combination of clinical experience and interpretations in the individual included studies.

We considered a p value of less than 0.1 as statistical significance for heterogeneity between studies [23]. We considered I² ≤ 40 as low heterogeneity, I² > 40–75 % moderate and I² > 75 % substantial heterogeneity [17]. In instances of lack of statistical significance for an overall effect, confidence intervals were assessed for potential trends that may suggest movement towards an increase or decrease in overall effect. In instances of statistical significance for heterogeneity, we performed sensitivity analyses and explained potential reasons for heterogeneity.

All 24 included studies were randomized controlled trials. Fifteen studies included a non-exercising control group [26, 27, 29, 31, 32, 36, 38, 40, 42, 46‐51]. Eight studies included co-intervention groups, comparing exercise plus diet or nutritional counselling versus diet or nutritional counselling only (Terry [52] low lipid diet; Ogalha [28] nutritional counselling; Balasubramanyam [33] low lipid diet plus exercise recommendation; Agostini [34] standard diet); exercise plus metformin versus metformin only (Driscoll [44]; Fitch [31]) exercise plus testosterone enanthate versus testosterone only (Grinspoon [42]) and exercise plus pioglitazone versus pioglitazone only (Yarasheski [25]). One study included a non-exercising counselling group (exercise vs. counselling group) [47]; two studies included a progressive resistive exercise (PRE) group compared with an aerobic exercise group [30, 38]; and two studies had comparison groups that compared heavy with moderate exercise [53, 54]. In 18 studies exercise was described as supervised [25‐28, 30‐33, 38, 40, 42, 44, 46‐48, 50‐52] and in the remaining four studies, the level of supervision was not stated. Two of the studies involved a supervised home-based exercise intervention [50, 51] and one study involved a combination of exercise at a rehabilitation center (supervised once per week) and home-based exercise (un-supervised three times per week) [29]. Ten studies involved exercise at a supervised facility such as a hospital [25, 44], medical or rehabilitation center [29, 40], exercise facility, fitness or wellness centre [26, 28, 30, 46], gymnasium [33], or prison [27]; whereas the location of exercise was not specified in the remaining 12 studies.

A total of 1242 participants were included in the review (number of participants in included studies at baseline). Participants included adults living with HIV at various stages of HIV infection, with CD4 counts ranging from <100 cells/mm³ to greater than 1000 cells/mm³. Studies included both men and women, with women comprising approximately 22 % of the total number of participants at study completion. The mean age of the participants in the included studies ranged from 30 to 49 years (inclusion criteria ranged from 18 to 65 years of age).

Four studies (17 %) were published prior to introduction of combination antiretroviral therapy (prior to 1996) [36, 38, 47, 53] followed by six (25 %) between 1998 and 2002 [40, 42, 48‐50, 54], six (25 %) between 2004 and 2008 [27, 30, 44, 46, 51, 52] and eight (33 %) between 2009 and 2013 [25, 26, 28, 29, 31‐34]. The majority of participants in 14 studies were taking combination antiretroviral therapy including 72 % [42]; 82 % [51] and 100 % on highly active antiretroviral therapy [25, 26, 28‐34, 44, 46, 52]. Smith [40] reported 23 % of participants were taking protease inhibitors and all other participants were on some form of antiretroviral therapy. Five studies included participants who were not on combination antiretroviral therapy; however, others reported including participants taking some form of antiretroviral medication [38, 48‐50] (Table 1).

Eleven studies included participants living with additional health-related conditions (in addition to HIV). Nine studies included participants with forms of hyperlipidemia [52], dyslipidemia [30, 33], lipodystrophy [28, 30], changes in fat distribution [44, 46, 51], hyperinsulinemia [44], insulin resistance, glucose intolerance and central adiposity [25], and metabolic syndrome [31]. One study included participants with AIDS wasting [42]. One study included participants who were co-infected with Hepatitis C and on methadone maintenance who were prison inmates [27]. Other personal characteristics were reported inconsistently across studies (Table 1).

All except two included studies (92 %) assessed immunological or virological outcomes or both, in the form of CD4 count or viral load [29, 34]. Twenty of the 24 included studies (83 %) assessed cardiorespiratory outcomes [26‐28, 30‐33, 36, 38, 40, 44, 46‐54]. Eleven of the 24 included studies (46 %) assessed strength outcomes [26, 27, 30‐32, 38, 42, 44, 47, 48, 51]. Eighteen of the 24 included studies (75 %) assessed weight and body composition outcomes [25‐28, 30‐34, 38, 40, 42, 44, 46, 48, 51, 52, 54]. Thirteen of the 24 included studies (54 %) assessed psychological outcomes in the form of anxiety and depression, health status, depression, mood and life satisfaction, and health-related quality of life [26‐29, 36, 38, 40, 46, 48‐50, 53, 54]. Safety in the form of monitoring adverse events was reported in nine of the 24 studies (38 %) [25, 27, 29, 31‐33, 47, 48, 51] (Table 2).

We wrote to authors of 11 included studies for clarification and additional data, three of whom responded. Yarasheski provided additional data including mean change and standard deviations of body mass index outcomes and viral load outcomes [25]. Agostini clarified the intervention included a combination of aerobic and resistive exercise and provided more details on the intervention. Authors indicated they were not able to provide raw data on body weight, fat mass, muscle mass, or waist circumference (data were reported as % increase or decrease) [34]. We requested SF-36 Physical Component Scores (PCS) and Mental Component Scores (MCS) from Tiozzo who responded with data on the eight SF-36 sub-scale scores [26].

An overview of risk of bias of included studies is provided in Fig. 2. We describe details of potential bias of included studies below.

Overall 303 participants withdrew from the included studies resulting in an overall ~24 % withdrawal rate (303/1242 participants at baseline). Withdrawal rates within individual studies ranged from 0 % [32, 38] to 76 % [53] (Table 1). Overall a high risk of attrition bias exists as 16 of the 24 included studies (67 %) reported withdrawal rates >15 %. The remaining eight included studies had low risk of attrition bias (33 %) with withdrawal rates less than 15 % [25, 28, 30, 32, 34, 38, 46, 51] (Fig. 2).

Withdrawal rates were similar between comparison groups for the majority of included studies. Three studies reported differences in the characteristics of participants who withdrew from the study [29, 33, 50] with more women and/or African Americans withdrawing from two studies [29, 50] and older participants with less familial history of diabetes remaining in the other study [33]. Twenty-three of the 24 included studies (96 %) made reference to participants who withdrew from or were non-adherent (or non-compliant) with the intervention. Withdrawal rates were not reported by LaPerriere [36]. Rates of withdrawal for individual studies are provided in Table 1.

Adherence to the exercise intervention was reported in nine of the 24 included studies (38 %) with adherence rates ranging from 61 % to 100 % [25‐27, 30, 32, 46, 48, 51, 52]. Mutimura [45] reported an 82 % adherence rate and [48] reported 61 % of participants were adherent with the exercise intervention. Both studies defined adherence as attending >50 % of the exercise sessions [46, 48]. Farinatti [32] reported an 87 % adherence rate; Yarasheski [25] a 92 % adherence rate; and Perez-Moreno [27] an overall adherence rate to the intervention of 71 % [25, 27, 32]. Terry [52] reported that adherence to the exercise sessions was 100 % in both groups [52]. Dolan [51] reported that participants in the exercise group completed 96 % of the total exercise interventions. Tiozzo [26] reported that participants in the exercise group attended on average 81 % of the supervised exercise sessions [26]. Lindegaard [30] reported that adherence to exercise was 99 % and 96 % in the aerobic and resistive exercise groups, respectively. All nine of the studies that reported on adherence also supervised the exercise intervention [25‐27, 30, 32, 46, 48, 51, 52]. MacArthur [53] reported six out of 25 of the participants were compliant with the exercise program (attended >80 % of the sessions), seven were somewhat compliant (attended 30–80 % of sessions) and 12 were not compliant (attended <30 % of sessions) [53]. Supervision of the exercise intervention was not reported in this study.

Overall a low risk of reporting bias exists as the majority of included studies; 20/25 (83 %) were free of selective outcome reporting as authors provided data on all pre-specified outcomes. Four studies (17 %) had incomplete or inconsistent data [28, 33, 34, 53]. Agostini [34] provided outcome data for body weight, fat mass, muscle mass and waist circumference in % increase or decrease only. Authors responded to our request stating that they did not have access to the raw data. Balasubramanyam [33] did not report all outcomes for body composition and cardiorespiratory fitness. MacArthur [53] only reported on six of the participants who were compliant with the exercise intervention [53]. In Ogalha [28], the data across tables are inconsistent and authors did not report data for all outcomes such as viral load (Fig. 2).

Overall a low risk for other sources of potential bias exists as the majority of studies (92 %) appeared free from other problems that could place a study at high risk of bias. Two studies possessed unclear risk of additional bias [32, 33]. Balasubramanyam [33] reported receiving > $10,000 funding from Abbott and research support from consultancy fees [33]. In Farinatti [32], a higher number of participants were assigned to the exercise group to maintain the sample size at study completion if adherence to exercise was low; it is unclear if this may have skewed results [32].

Seventy-five meta-analyses were completed across eight sub-group comparisons in this review (17 of which included similar studies) resulting in 58 unique meta-analyses to this systematic review. Meta-analyses were performed for immunological and virological outcomes (CD4 count, CD4 percentage, and viral load), cardiorespiratory outcomes (VO2max, HRmax, exercise time), strength outcomes (chest press, leg press, knee extension, knee flexion, upper and lower body strength), weight and body composition outcomes (body weight, body mass index, lean body mass, fat mass, percent body fat, leg muscle area, waist circumference, hip circumference, waist-to-hip ratio), and psychological outcomes (quality of life, depression-dejection symptoms).

Of the 58 unique meta-analyses, 28 were new to this systematic review update, 16 were updated with additional studies, and 14 were the same as in the previous review [10]. Subgroup comparisons of the meta-analyses included 1) constant or interval aerobic exercise or combined aerobic and progressive resistive exercise (PRE) versus no exercise; 2) constant or interval aerobic exercise versus no exercise; 3) constant aerobic exercise versus no exercise; 4) interval aerobic exercise versus no exercise; 5) moderate-intensity aerobic exercise versus heavy-intensity aerobic exercise; 6) constant or interval aerobic exercise combined with PRE versus no exercise; 7) aerobic exercise versus PRE; and 8) combined aerobic exercise and diet and/or nutrition versus diet and/or nutrition only.

Fifteen of the 24 included studies compared constant or interval aerobic exercise or combined aerobic and progressive resistive exercise (PRE) with a non-exercising control group [26, 27, 29, 31, 32, 36, 38, 40, 42, 46‐51]. Eight studies compared constant or interval aerobic exercise with a non-exercising control group [29, 36, 38, 40, 46, 48‐50]. Seven studies compared combined aerobic and PRE [26, 27, 31, 32, 42, 47, 51]. Two studies compared aerobic with PRE [30, 38]. Three studies did not include a non-exercising control group [30, 53, 54] (Table 1). Driscoll [44] and Fitch [31] included aerobic and PRE combined with metformin compared with metformin only but we were unable to combine outcomes in meta-analysis. Terry [52], Ogalha [28], Balasubramanyam [33], and Agostini [34] included aerobic exercise or aerobic combined with PRE combined with a lipid diet and/or nutrition counselling versus diet and/or nutritional counselling alone. Yarasheski [25] included aerobic and PRE combined with pioglitazone versus pioglitazone only (Table 1).

The number of meta-analyses was limited due to variability in types of exercise interventions (aerobic exercise vs. combined aerobic and PRE exercise), level of exercise supervision, types of outcomes reported, and methodological quality. Aerobic interventions in the trials varied according to constant compared to interval exercise and moderate compared to heavy intensity exercise, and combined aerobic and resistive exercise compared to aerobic exercise alone. See Table 1 for characteristics of included studies and descriptions of specific interventions in individual studies.

Twenty-two of the 24 included studies (92 %) assessed immunological or virological outcomes, or both, in the form of CD4 count or viral load. Fourteen of the studies included a non-exercising control group, seven of which included combined interventions of aerobic and PRE [26, 27, 31, 32, 42, 47, 51]. Seven studies also measured immunological and virological outcomes but did not include a non-exercising control group [25, 28, 33, 44, 52‐54].

Twenty of the 24 included studies (83 %) assessed cardiorespiratory outcomes, 13 of which compared aerobic or combined aerobic and PRE to non-exercise [26, 27, 31, 32, 36, 38, 40, 46‐51]; seven of which compared constant or interval aerobic exercise to non-exercising control [36, 38, 40, 46, 48‐50], three of which compared moderate aerobic exercise with heavy aerobic exercise [49, 53, 54], and six of which compared constant or aerobic exercise and PRE to non-exercising control [26, 27, 31, 32, 47, 51]. Driscoll [44] and Fitch [31] measured cardiorespiratory outcomes but compared exercise to metformin. Terry [52], Ogalha [28], and Balasubramanyam [33] measured cardiorespiratory outcomes but compared exercise combined with diet and/or nutritional counselling (Table 1).

We have very little confidence in the effect estimate demonstrating a significant increase of 2.87 ml/kg/min for VO2max comparing aerobic exercise (or combined aerobic and PRE) with non-exercising control. The true effect is likely to be substantially different from the estimate of effect (Table 4). This outcome was downgraded from high to very low on the GRADE quality of evidence due to incomplete outcome data (withdrawals of included studies >15 %), suspected publication bias, substantial heterogeneity (I² = 67 %); and because the lower level of the confidence interval did not cross the estimated clinically important change in VO2max (despite the estimate surpassing our hypothesized clinically important change in VO2max of 2 ml/kg/min) (see Additional file 2 – GRADE Summary of Findings Table).

Eleven of the 24 included studies (46 %) assessed strength outcomes [26, 27, 30‐32, 38, 42, 44, 47, 48, 51]. Ten meta-analyses were performed, four of which included duplicate studies. Meta-analyses demonstrated significant improvements in upper and lower body strength as measured by increases in 1-repetition maximum for chest press, and knee flexion; and a non-significant improvement (trend) towards increases in 1-RM for leg press and knee extension for participants in the combined aerobic and PRE group versus non-exercising control group (Table 5). Two meta-analyses were conducted comparing aerobic versus resistive exercise. Significantly greater increases in strength were found among participants in the PRE group compared with participants in the aerobic exercise only group for upper and lower muscle groups (Table 5).

All six point estimates for upper and lower extremity strength are greater than 2 kg and 5 kg respectively indicating a clinically important greater increase in strength for resistive exercisers compared with aerobic exercise.

Our confidence is limited in the effect estimate of a significant increase of 11.86 kg for 1-repetition maximum for chest press comparing aerobic exercise (or combined aerobic and PRE) with non-exercising control. The true effect may be substantially different from the estimate of effect (Table 5). This outcome was downgraded from high to low on the GRADE quality of evidence due to incomplete outcome data (withdrawals of included studies were >15 %), publication bias suspected, and moderate heterogeneity (I² = 46 %). However, the estimate demonstrated a significant effect for improvement in chest press and the lower limit of the confidence interval surpassed our hypothesized clinically important change in upper body strength (see Additional file 2 – GRADE Summary of Findings Table).

We have very little confidence in the effect estimate of a non-significant increase of 50.96 kg for 1-repetition maximum for leg press comparing aerobic exercise (or combined aerobic and PRE) with non-exercising control. The true effect is likely to be substantially different from the estimate of effect (Table 5). This outcome was downgraded from high to very low on the GRADE quality of evidence due to incomplete outcome data (withdrawals of included studies were >15 %), publication bias was suspected, and there was considerable heterogeneity (I² = 88 %). Furthermore, the confidence intervals cross the clinically important improvement and deterioration for change in lower body strength (see Additional file 2 – GRADE Summary of Findings Table).

Eighteen of the 24 included studies assessed weight and body composition outcomes [25‐28, 30‐34, 38, 40, 42, 44, 46, 48, 51, 52, 54].

We are moderately confident in the effect estimate of a non-significant increase of 0.38 kg for body weight comparing aerobic exercise (or combined aerobic and PRE) with non-exercising control. The true effect is likely to be close to the estimate of effect; but there is a possibility that it is substantially different (Table 6). This outcome was downgraded from high to moderate on the GRADE quality of evidence due to incomplete outcome data (withdrawals of included studies were >15 %), and moderate heterogeneity (I² = 48 %). The confidence interval limits and effect estimate do not cross our estimated clinically important change in body weight (see Additional file 2 – GRADE Summary of Findings Table).

We are very confident with the effect estimate of a non-significant increase of 0.07 kg/m² for body mass index comparing aerobic exercise (or combined aerobic and PRE) with non-exercising control. The true effect is likely to be close to the estimate of effect; but there is a possibility that it is substantially different (Table 6). This outcome was not downgraded on the GRADE quality of evidence because this was an objective outcome of interest and publication bias was not suspected (see Additional file 2 – GRADE Summary of Findings Table).

Thirteen of the 24 included studies (54 %) assessed psychological outcomes in the form of anxiety and depression, health status, depression, mood and life satisfaction, and health-related quality of life [26‐29, 36, 38, 40, 46, 48‐50, 53, 54].

We have very little confidence in the effect estimate demonstrating an improvement of 6.47 in SF-36 sub scale scores comparing aerobic exercise (or combined aerobic and PRE) with non-exercising control. The true effect is likely to be substantially different from the estimate of effect (Table 7). This outcome was downgraded from high to very low on the GRADE quality of evidence due to incomplete outcome data (withdrawals of included studies were >15 %), publication bias was suspected, and due to variable heterogeneity on specific meta-analyses of sub scales ranging from (I² = 0 to 87 %). Nevertheless, the estimates for mental health, role emotional and physical function SF-36 sub scales surpass the estimated clinically important improvement in quality of life of 10 points; whereas the other 5 statistically significant sub scale analyses do not surpass the clinically important improvement estimate (see Additional file 2 – GRADE Summary of Findings Table).

Safety in the form of monitoring adverse events was reported in 12 of the 24 studies (38 %) [25, 27, 29, 31‐33, 40, 42, 47‐49, 51] (Table 2). Meta-analysis was not possible due to the scarcity and variability of reporting adverse events. Adverse events were reported in five of the 24 studies, none of which were attributed to exercise or considered serious [31, 33, 47, 48, 51]. Rigsby [47] reported one death during the study in the counselling group; however, the death was not attributed to the exercise intervention. Perna [48] reported one hospitalization during the course of the study [48]. Dolan [51] reported that one participant in the exercise group had an exacerbation of asthma and one participant in the non-exercising group experienced chest pain at baseline . Balasubramanyam [33] indicated that adverse events (such as headaches, dizziness, flushing, diarrhea, nausea and vomiting and fatigue) were infrequent and events appeared to be similar across the comparison groups. Fitch [31] reported two participants in the exercise group experienced muscle strains related to the resistance training requiring modification of weights. Otherwise, no serious adverse events were reported and the exercise program was well tolerated.

Three studies reported no serious adverse events, health problems, or complications [25, 27, 32]. Two studies reported that no participants withdrew due to illness or infection [40, 49]. Grinspoon [42] reported having no reported deaths, adverse events or side effects during the course of the study. Maharaj [29] reported that none of the participants showed any adverse effects on their clinical status of CD4 counts, viral load, or increase in opportunistic infections, heart, respiratory and blood pressure either during or after the exercise intervention. The other studies did not report on any outcomes of adverse events (Table 2).

Evidence about the safety and effectiveness of aerobic exercise for adults living with HIV is increasing, including narrative and systematic reviews, and clinical guidelines that support aerobic exercise interventions in the context of HIV [63‐71]. Recent evidence-informed guidelines also highlight the potential benefits and role of aerobic and resistive exercise for older adults living with HIV [55, 72, 73].

Interpretations of weight and body composition outcomes should be considered relative to the publication dates of the included studies. Prior to the advent of combination antiretroviral therapy, studies on exercise tended to include participants with AIDS-wasting, whereas recent evidence includes participants on combination antiretroviral therapy with lipodystrophy, body fat redistribution, or hyperinsulinemia. These studies commonly assessed the impact of exercise on weight, body composition, and metabolic outcomes, and reflect our inclusion of weight and body composition in this review. Furthermore, an increasing number of studies include interventions with a combination of resistive and aerobic exercise, which led us to consider the effectiveness of combined PRE and aerobic exercise with non-exercise. We observed an increase in the number of studies that assessed interventions such as tai chi [74, 75] or co-interventions with exercise such as diet and/or nutritional counselling [28, 33, 34, 52] metformin [31, 44] and pioglitazone [25]. Finally, this review included only 22 % of women participants reflecting a largely under-represented population in the HIV and exercise literature.

Future studies should make efforts to include all participants in an “intent-to-treat” analysis, blind assessor of outcomes, and include clinically meaningful and standardized outcomes to strengthen existing meta-analyses. As the population living with HIV ages, future research should include older adults and those living with multiple concurrent health conditions such as cardiovascular disease, liver disease, kidney disease, and bone and joint disorders. As the HIV and exercise literature expands, future updates of this review should assess the impact of exercise co-interventions, the impact of exercise on outcomes including functional status and metabolic or inflammatory markers and make an attempt to conduct sub-group analyses to acknowledge the changing health-related consequences associated with the pre versus post-combination antiretroviral era. Finally, given the majority of studies (18/24) included exercise interventions in clinical settings supervised by health care or research personnel, future research may consider evaluating the effect of non-supervised exercise interventions or community-based fitness programmes that may reflect a self-management model of community-based exercise for people with HIV [76].