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Effects of Aerobic and Resistance Exercise on Cardiovascular Parameters for People Living With HIV

A Meta-analysis

Zech, Philipp, Dipl*; Pérez-Chaparro, Camilo, MD; Schuch, Felipe, PhD; Wolfarth, Bernd, MD, PhD; Rapp, Michael, MD, PhD; Heissel, Andreas, PhD

Journal of the Association of Nurses in AIDS Care: March-April 2019 - Volume 30 - Issue 2 - p 186–205
doi: 10.1097/JNC.0000000000000006
Research Article
Free

People living with HIV (PLWH) have limited exercise capacity because of anemia, neuromuscular disorders, and pulmonary limitations. We used a meta-analysis to examine the effect of aerobic and resistance exercise alone and in combination on cardiovascular parameters. Subgroup meta-analyses were conducted and long-term effects of exercise were investigated. A systematic literature search was conducted up to July/August 2017. The Physiotherapy Evidence Database-scale was used to rate quality and assess the risk of bias on the papers. Standardized mean differences (SMDs) were calculated to assess the effect of exercise. Posttreatment comparison between the exercise and control groups revealed moderate and large effect sizes in favor of the intervention group for VO2max (SMD = 0.66, p < .0001) and the 6-minute walk test (SMD = 1.11, p = .0001). Exercise had a positive effect on cardiovascular parameters in PLWH. Exercise can be a prevention factor for PLWH dealing with multiple comorbidities.

Philipp Zech, Dipl, is a PhD Student and Sport Scientist, Social and Preventive Medicine, Department of Exercise and Health Sciences, University of Potsdam, Potsdam, Germany. Camilo Pérez-Chaparro, MD, is a Physician in Sport Medicine and PhD Student, Post Graduate Program in Health and Human Development, La Salle University, Canos, Brazil. Felipe Schuch, PhD, is a Professor and Sport Scientist, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. Bernd Wolfarth, MD, PhD, is Professor and Physician in Sport Medicine, Department of Sports Sciences, Division of Sports Medicine, Humboldt University of Berlin, Berlin, Germany. Michael Rapp, MD, PhD, is Professor and Physician in Psychiatry, Social and Preventive Medicine, Department of Exercise and Health Sciences, University of Potsdam, Potsdam, Germany. Andreas Heissel, PhD, is a Research Fellow and Sports Scientist, Social and Preventive Medicine, Department of Exercise and Health Sciences, University of Potsdam, Potsdam, Germany.

Corresponding author: Philipp Zech, e-mail: phzech@uni-potsdam.de

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article

In 2015, the Joint United Nations Programme on HIV/AIDS (2016) estimated that 36.7 million people were living with HIV; 34.9 million were adults older than 25 years, only 17 million of whom were receiving antiretroviral drug therapy (ART; UNAIDS, 2016). Because of advances in ART, people living with HIV (PLWH) have been exceeding their expected life spans. Gueler et al. (2016) found that life expectancy for PLWH increased up to 43.1 years when treated early. This increase in life expectancy because of ART, along with HIV itself, has predisposed PLWH to develop comorbidities such as metabolic syndrome, diabetes, and cardiovascular diseases (Young, Critchley, Johnstone, & Unwin, 2009), limiting age-predicted fitness performance, oxygen consumption (VO2max), grip strength, chair raise time, and walked distance, which are reflected in the independent activities of daily living for PLWH (Erlandson, Schrack, Jankowski, Brown, & Campbell, 2014). Similarly, increased life expectancy predisposes PLWH to age-related cardio-metabolic diseases. In a cohort including 8,762 PLWH from 70 centers across Europe, Argentina, and Israel, different comorbidities such as hypertension (32.1%), high cholesterol (45.0%), and overweight (27.1%) were found. In the same cohort, 17.2% of the PLWH had a 5-year cardiovascular risk of more than 5% (Shahmanesh et al., 2016). In a Spanish cohort including 224 PLWH, 95% of the participants had at least one comorbidity; 37.9% had dyslipidemia, 21.9% had diabetes mellitus or impaired fasting glucose, and 21.9% were hypertensive (García Gonzalo, Santamaría Mas, Pascual Tomé, Ibarguren Pinilla, & Rodríguez-Arrondo, 2016). In addition, male PLWH in North America have been shown to be 1.5 times more likely to have a chronic disease (Friedman & Duffus, 2016).

HIV infection primarily affects the immune system, especially CD4+ T helper cells (Imran et al., 2016). However, other body systems, organs, and structures, such as body composition and muscle mass, are also directly affected by HIV and/or ART. For instance, PLWH have demonstrated limited exercise capacity because of anemia, neuromuscular disorders, and pulmonary limitations (Cade, Peralta, & Keyser, 2004). HIV infection also increases the risk of cardiovascular diseases through different mechanisms: elevated cytokine levels, chronic vascular inflammation, and endothelial dysfunction (Chu & Selwyn, 2011). Antiretroviral drug therapy is related to high systolic/diastolic blood pressure (SBP/DBP) and a higher risk of hypertension (Nduka, Stranges, Sarki, Kimani, & Uthman, 2016).

Wasting syndrome has been associated with lowered strength performance and an inability to perform activities of daily living (Grinspoon et al., 1999 ; Wilson et al., 2012). Another muscle-associated problem is myalgia, which is twice as common in PLWH regardless of ART use compared with uninfected controls (Fox & Walker-Bone, 2015). Aerobic exercise (AE), resistance training (RT), and AE combined with RT (AERT) are linked to improvements in maximal oxygen consumption and blood pressure, lower risk of age-related cardiovascular and metabolic diseases, muscle mass maintenance, improved muscle strength maintenance, and weight gain in general (Garber et al., 2011 ; Valkeinen, Aaltonen, & Kujala, 2010 ; Wilson et al., 2012).

The beneficial effects of exercise in PLWH have been the focus of various systematic reviews and meta-analyses (Gomes-Neto, Conceição, Oliveira Carvalho, & Brites, 2013 , 2015 ; O'Brien, Tynan, Nixon, & Glazier, 2008 , 2016). These studies investigated the effects of AE with or without the combination of RT versus no exercise on the maximal oxygen consumption and muscle strength of PLWH.

A difference in favor of exercise-intervention groups was found for VO2max (Gomes-Neto et al., 2015 ; O’Brien et al., 2016). Gomes-Neto et al. (2015) showed a significant effect in VO2max with a weighted mean difference = 4.48, p < .0001, including five studies published up to the year 2014. O’Brian et al. (2016) also showed an effect in VO2max, p < .0001, evaluating eight studies published up to April 2013.

Recent randomized controlled trials (RCTs; Anandh, Ivor, & Jagatheesan, 2014 ; Ezema et al., 2014 ; Mangona et al., 2015 ; McDermott et al., 2017 ; Patil, Shimpi, Rairikar, Shyam, & Sancheti, 2017 ; Pedro et al., 2016 ; Roos, Myezwa, van Aswegen, & Musenge, 2014 ; Shah et al., 2016 ; Zanetti et al., 2016) have been published, and an up-to-date systematic review and meta-analysis of the effect of exercise on cardiorespiratory parameters of PLWH would be valuable. In our systematic review and meta-analysis, we investigated the long-term effects of exercise on cardiorespiratory fitness (VO2max), the 6-minute walk test (6MWT), maximum heart rate (HRmax), resting heart rate (RHR), SBP and DBP, and maximum power output (Wmax). Unique to our systematic review is the analysis of cardiovascular parameters 6MWT, RHR, and Wmax, which have not been analyzed before. The aims of our study were as follows: (a) to investigate the effects of AE, RT, and AERT on cardiovascular health markers in PLWH; and (b) to perform subgroup analyses investigating the role of exercise type (aerobic and resistance exercise alone, combined training), professional supervision, exercise frequency and duration (150 minutes of exercise per week), the control group (active low-intensity; exercising control groups excluded), and high-quality studies (PEDro score ≥ 5).

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Methods

We conducted a systematic review and meta-analysis of quantitative meta-analyses of randomized controlled studies using the Cochrane Collaboration protocol as a principle. The study was registered on the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=42438) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Moher, Liberati, Tetzlaff, & Altman, 2009).

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Search Procedures

The literature search was performed through five databases: PubMed, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, the PEDro (Physiotherapy Evidence Database), and Web of Science from inception to July/August 2017. Search parameters and syntax were adapted to the requirements of each database. Combined MeSH terms and text words were related to exercise and physiological parameters. The clinicaltrial.gov database was used to identify ongoing studies with the following syntax: (HIV infection HIV AND exercise AND physiologic OR muscle) and (HIV AND exercise AND cardiovascular). In addition, tables, reference lists of the contents of relevant literature, and books were screened.

Two authors independently screened and recorded the results for each title for potential relevance as set by the eligibility criteria (below). If an article passed the title screening process, the abstracts were then screened. After passing both of these assessment steps, full-text articles were obtained and independently assessed by the same two authors. When disagreement arose, the authors discussed their differences until an agreement could be reached. If this was not possible, a third author was consulted to determine the final decision.

To achieve a high number of relevant studies, the search terms were expanded to include non–cardiovascular parameters and RT alone. Studies not investigating any cardiovascular parameters were later excluded (Figure 1).

Figure 1

Figure 1

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Inclusion and Exclusion Criteria

Randomized controlled trials comparing AE, RT, and AERT against a non–exercising control group published in the English language were considered for inclusion. The studies had to involve PLWH at any stage of infection, who were at least 18 years old, male or female, with or without comorbidities, and additionally investigating at least one of the following cardiovascular parameters: VO2max, 6MWT, HRmax, RHR, SBP, DBP, or Wmax, regarding either endurance or strength performance. Aerobic exercise was defined accordingly as “sustained repetitive physical activity, such as walking, dancing, cycling, and swimming, that elevates the heart rate and increases oxygen consumption resulting in improved functioning of cardio-vascular and respiratory systems” (Mosby, 2013), performed two or more times per week for at least 4 weeks. Resistance training was defined as “any form of I think physical activity that is designed to improve muscular fitness by exercising a muscle or a muscle group against external resistance” (Esco, 2013, p. 1), performed two or more times per week for at least 4 weeks. Alternative exercise programs (i.e., Tai Chi, Qi Gong, and Yoga) were excluded because trials incorporating these exercise programs have a significantly higher heterogeneity (I 2 = 58%, χ2 = 18.97, p = .02) when compared with conventional exercise (Bridle, Spanjers, Patel, Atherton, & Lamb, 2012 ; Schuch et al., 2016). Because an increase in VO2max after RT depends on the initial VO2max (Ozaki, Loenneke, Thiebaud, & Abe, 2013), and greater changes on VO2max are achieved through AE compared with other training modes (Valkeinen et al., 2010), we decided that if a study involved two or more different exercise interventions, only the AE group would be used for the main meta-analysis.

Eligible non–exercising control group conditions in addition to the usual treatment were placebo control groups, social contact control groups, protein or steroid supplement control groups, exercise recommendations, counseling, recreational activities, and exercise groups performing light activities such as walking or stretching. An RCT was accepted if the allocation of the participants to the intervention or control group was explicitly described as randomized and the eligibility criteria were specified. Studies in which the participants were supervised by a physiologist, physiotherapist, or a fitness trainer were eligible for the subgroup analyses for professional supervision.

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Risk of Bias

The PEDro scale (Maher, Sherrington, Herbert, Moseley, & Elkins, 2003) was used to determine the level of quality and assess the risk of bias of the included studies. Two authors independently assessed the risk of bias. The PEDro scale consisted of 11 criteria in which the first criterion of eligibility was marked with a yes or no. If the study had no eligibility criteria, the study was excluded. The rest of the criteria were marked with a checkmark or a 0. Discrepancies between the two reviewing authors were resolved by consulting a third author. The results of the bias risk assessment are shown in Table 1.

Table 1

Table 1

Blinding can be difficult or impossible and is less frequently reported in non–pharmacological treatment RCTs (Boutron et al., 2007). For this reason, the total PEDro score for RCTs involving exercise can be affected, thus achieving PEDro scores lower than six, even if the other criteria are satisfied (Moseley, Herbert, Sherrington, & Maher, 2002). We therefore classified studies with a PEDro score of at least five as high-quality studies (Maher et al., 2003 ; Moseley et al., 2002 ; Sherrington, Herbert, Maher, & Moseley, 2000).

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Data Extraction

Data were extracted independently by two authors. Different measuring units, such as mean ± standard error or mean ± change/difference (post minus pre), were converted to mean ± standard deviation (SD) independently by the two authors. In case the measuring unit was not convertible or relevant data were missing in the study, the author of the original study was contacted via email. If 2 weeks passed without an answer from the author, the author was kindly reminded, and the co-authors were contacted via email. When no email address in the study was reported, the author was looked up in Google and Research Gate and contacted. If the author did not reply, or did not have the missing data or an adequate conversion of the measuring unit, the study was excluded from the quantitative synthesis.

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Data Analysis

Review Manager 5.3 was used for the meta-analysis. Parameters were analyzed together for AE, RT, and AERT. Whenever possible, subgroup analyses were performed, evaluating the effects of AE alone, AERT alone, professionally supervised training, at least three training sessions per week, 150 minutes of exercise per week, active exercising control groups excluded, and high-quality studies with a PEDro score of at least 5. Main outcome variables of mean, SD, and number of participants for postmeasures were used in the meta-analyses. No meta-analysis was conducted if a parameter was investigated only once. When calculating standardized mean differences (SMD) in meta-analyses, the random effect model was used for postintervention measurement comparison between the exercise and control groups (Borenstein, Hedges, Higgins, & Rothstein, 2010 ; DerSimonian & Laird, 1986 ; Higgins, Thompson, Deeks, & Altman, 2003). An overall effect with a p-value less than 0.05 was considered statistically significant (Higgins et al., 2003). Effect size was interpreted using the cutoff defined by (Cohen 1992; d = 0.20 small, 0.50 medium, 0.80 large).

Variation in the size of treatment effects across all trials, or heterogeneity, was determined by calculating I 2 statistics (Higgins et al., 2003). Three ranges of heterogeneity were considered: (a) I 2 of 24% or lower for low heterogeneity, (b) I 2 of 25% to 74% for moderate heterogeneity, and (c) I 2 of 75% or higher for high heterogeneity.

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Results

Search Results

We retrieved a total of 398 citations through the search described in the Methods section. After screening the titles, 231 citations were excluded because of ineligible focus. After reading the remaining 167 citation abstracts, 50 citations were excluded for the following reasons: exercise was compared with exercise (n = 9), the language was not English (n = 4), the intervention group or control group was partially or totally integrated with HIV-uninfected participants (n = 6), the desired outcomes were not addressed (n = 11), or the citations did not refer to any RCTs (n = 13) or reviews (n = 7). The remaining 117 citations were screened before the full text was acquired, and 66 citations were found to be duplicates. The full texts of 51 studies were read and 16 additional studies were excluded: one study's intervention group performed a form of acute exercise, one study's control group performed exercise, two studies did not investigate exercise at all, two studies' intervention groups or control groups were partially or totally integrated with HIV-uninfected participants, five studies did not investigate the desired outcomes, and five were not RCT studies. In total, 36 studies from the systematic search, and four studies added through cross-referencing citations (n = 40), met the eligibility criteria and were considered relevant for inclusion in the meta-analysis. Three studies were then excluded because of lack of reply from the authors after contacting them twice, and eight studies did not investigate cardiovascular parameters. A total of 28 studies evaluated cardiovascular outcomes (Figure 1).

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Studies and Participant Characteristics

In total, 28 studies met the eligibility criteria and were considered relevant for inclusion in our systematic review and meta-analysis. Two studies (Lox, MeAuley, & Tucker, 1995 , 1996) had shared results and used the same participants and intervention; these studies were summarized as one: Lox et al. (1995), (1996). For this reason, the total number of included studies resulted in 27 studies. In Table 2, studies included in our meta-analysis were given a coding number. Eleven studies (40.7%; 1, 2, 6, 11, 13, 15, 19, 20, and 22–24) investigated AE, 15 studies (55.6%; 3–5, 7–10, 12, 14, 16–18, 21, 25, and 26) investigated AERT, and one study (3.7%) investigated resistance exercise only (Zanetti et al., 2016). Ten studies (37.0%; 3–5, 7, 11, 13, 15, 18, 25, and 26) professionally supervised their participants with a physiologist or physiotherapist, and five studies (18.5%; 1, 8, 12, 22, and 27) mentioned supervision without giving further information about who was supervising the participants. In one study, a physician supervised the participants (Jaggers et al., 2013), and in another study, the investigator supervised the participants (Terry et al., 2006). Ten studies (37.0%; 2, 6, 9, 12, 16, 17, 19–21, and 23) did not mention supervision at all. Active control conditions such as conventional therapy, phone calls for social contact, or counseling about the positive effect of exercise and nutrition were used in six studies (22.2%; 2, 3, 6, 10, 12, and 20). The control group in four studies (14.8%; 7, 15, 17, and 24) performed recreational activities or very low-intensity physical activity such as walking or stretching only. Sedentary activities and no lifestyle intervention control groups were identified in 15 studies (55.5%; 1, 4, 8, 11, 13, 14, 16, 18, 19, 21–23, and 25–27), and two studies (7.4%) applied drug administration or placebos without exercise that served as the control group (Cade et al., 2013 ; Fitch et al., 2012). Twenty-two studies (81.5%; 1–5, 7, 8, 11–15, 17–22, and 24–27) had participants exercise over a period of at least 12 weeks. In 17 studies (63%; 1, 3–5, 8, 10–12, 14–18, and 23–26), participants exercised at least 150 minutes per week. Four studies (14.8%; 10, 13, 21, and 27) did not mention the number of training minutes per session.

Table 2-a

Table 2-a

Table 2-b

Table 2-b

Table 2-c

Table 2-c

Table 2-d

Table 2-d

Table 2-e

Table 2-e

The number of participants in six studies was very small: Cade et al. (2013), intervention group (n = 8) and control group (n = 12); Fitch et al. (2012), intervention group (n = 10) and control group (n = 11); Hand et al. (2008), intervention group (n = 11) and control group (n = 10); McDermott et al. (2017), intervention group (n = 5) and control group (n = 6); Perna et al. (1999), intervention group (n = 11) and control group (n = 10); and Stringer, Berezovskaya, O’Brien, Beck, & Casaburi (1998), intervention group (n = 9) and control group (n = 8). All baseline measures of the intervention groups were similar to the baseline measures of the control groups. More detailed characteristics of the studies included in this meta-analysis are shown in Table 2.

The total number of participants in the 27 included studies was 1,294 at baseline and 1,006 postintervention; the dropout rate was 22.26%. Three studies (11.1%; 10, 11, 27) had no dropouts. The average age was 41.46 years (SD = 5.04) for the intervention groups and 40.99 years (SD = 5.93) for the control groups. In addition to HIV, 14 studies (51.9%; 3–5, 7, 8, 10, 14, 17, 18, 20, 21, 24, 26, and 27) included participants with health-related conditions other than HIV, and five studies (18.5%; 4, 8, 17, 26, and 27) included some participants with metabolic abnormalities (e.g., insulin resistance, diabetes Type 2, hypertension, and metabolic syndrome). Five studies (18.5%; 4, 5, 18, 20, and 24) included participants with HIV wasting syndrome, lipodystrophy, changes related to fat distribution, or low testosterone levels; one study (3.7%; 21) included participants with functional limitations; and one study (3.7%; 7) included participants with depression.

The participants investigated in the included studies were from the United States (n = 14 studies; 51.85%; 2–5, 8–11, 19, 21–23, 25, and 26), Brazil (n = 5 studies; 18.5%; 14, 15, 17, 24, and 27), India (n = 2 studies; 7.4%; 1, 16), and one study (3.7%) each in Australia (7), Ireland (13), Mozambique (12), Nigeria (6), South Africa (20), and Spain (18). For more detailed information about the countries in which the studies were conducted, see Table 2.

Only two studies (7.4%; 2 and 13) did not mention ART for the investigated participants. Information of the specification of drug subtypes was presented in nine studies (33.3%; 4, 5, 8, 17, 20, 21, 24, 25, and 26). In eight studies (26.6%; 1, 5, 7, 9, 11, 18, 22, and 23), not all of the investigated participants in the study were on ART. For more detailed information about the different ART intakes and HIV durations for intervention groups and control groups, see Table 2.

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Outcomes of Included Studies

The primary outcome of interest was VO2max. Secondary outcomes were 6MWT, HRmax, RHR, SBP, DBP, and Wmax. The most frequently investigated parameter was VO2max in 17 studies (63%; 2, 4–6, 8, 9, 11–17, 19, and 22–24), followed by SBP and DBP in 12 studies (44.4%; 3–6, 8, 10, 12, 20, and 24–27). Maximum and RHRs were investigated by five and four studies (18.5%; 7, 11, 18, 19, and 24; and 14.8%; 4, 15, 20, and 25), respectively. The 6MWT and Wmax were investigated by four and three studies (14.8%; 1, 5, 20, and 21; and 11.1%; 18, 19, and 23), respectively. For details of the parameters analyzed in each included study, see Table 3.

Table 3

Table 3

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Study Quality

Of the included studies, 18 were judged to be of good methodological quality and had a low risk of bias with a PEDro score of at least 5 (1–3, 5–8, 10, 12, 13, 15–18, 20, 21, 26, 27). The remaining nine studies were of low quality (high risk of bias). The bias risk analysis according to the PEDro scale is presented in Table 1.

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Meta-analysis

Seven main meta-analyses and 45 subgroup analyses were conducted. For all meta-analyses, we used the random effect model (Table 4). Details about how often an outcome was investigated and in which study it was investigated are shown in Table 3.

Table 4-a

Table 4-a

Table 4-b

Table 4-b

In sum, 17 studies (63%) investigated VO2max. Nine studies were high-quality studies with a PEDro score of at least 5 (2, 5–7, 12, 13, and 15–17). In all but one study (Hand et al., 2008), the participants exercised at least three sessions/week. In all but one study (Mangona et al., 2015), the participants exercised with supervision. An overall SMD of 0.66 (p < .00001) was found in favor of the exercise group. Statistical heterogeneity was moderate (I 2 = 53%), indicating that there was relatively moderate variation in the effect sizes across trials.

Seven subgroup analyses for VO2max were performed: (a) AE versus control: SMD = 0.60 (p = .003); (b) AERT versus control: SMD = 0.73 (p < .0001); (c) professional supervision: SMD = 0.48 (p = .05); (d) ≥3 sessions/week: SMD = 0.63 (p < .00001); (e) ≥150 min/week: SMD = 0.63 (p < .00001); (f) control groups without low exercise: SMD = 0.72 (p < .00001), and (g) high-quality studies PEDro ≥ 5: SMD = 0.68 (p = .003). For more detailed information, see Table 4.

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6-minute walk test

All studies that evaluated this outcome were high-quality studies. An overall SMD = 0.59 in favor of the exercise group was found. There was a significant overall effect (p = .02) of exercise compared with the control group at posttreatment. Subgroup analysis for training at least 3 times/week, at least 150 min/week, control groups without low exercise, and PEDro score of at least five showed a significant overall effect (SMD = 0.80, p = .002; SMD = 1.11, p < .001; SMD = 0.59, p = .02; SMD = 0.59, p = .02). Subgroup analyses for AE and AERT revealed no significant overall effects.

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Maximum heart rate

An overall SMD = −0.38 in favor of the exercise group was found. There was no significant overall effect (p = .43) of exercise compared with the control group at posttreatment. Subgroup analyses in AE, AERT, professional supervision, exercise at least three sessions/week, at least 150 min/week, control groups without low exercise, and PEDro score of at least five revealed no significant overall effects.

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Resting heart rate

An overall SMD = −0.29 was found in favor of the exercise group. There was no significant overall effect (p = .32) of exercise compared with the control group at posttreatment. Subgroup analysis for AERT showed an SMD = −0.91 and a significant overall effect (p = .006). Subgroup analyses for AE, professional supervision, exercise at least three sessions/week, at least 150 min/week, control groups without low exercise, and PEDro score of at least five revealed no significant overall effects.

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Systolic blood pressure

An overall SMD = −0.27 in favor of the exercise group was found. There was no significant overall effect (p = .09) of exercise compared with the control group at posttreatment. Subgroup analyses for AE, AERT, professional supervision, exercise at least three sessions/week, at least 150 min/week, control groups without low exercise, and PEDro score of at least five revealed no significant overall effects.

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Diastolic blood pressure

An overall SMD = 0.01 in favor of the exercise group was found. There was no significant overall effect (p = .89) of exercise compared with the control group at posttreatment. Subgroup analyses for AE, AERT, professional supervision, exercise at least three sessions/week, at least 150 min/week, control groups without low exercise, and PEDro score of at least five revealed no significant overall effects.

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Maximum power output

An overall SMD = 0.80 in favor of the exercise group was found. There was a significant overall effect (p = .009) of exercise compared with the control group at posttreatment. Subgroup analysis for 150 min/week revealed a significant overall effect (SMD = 1.06, p = .004). Subgroup analyses for AE and control groups without low exercise revealed no significant overall effect. Subgroup analyses for AERT and PEDro score of at least five were not possible. For more detailed information, see Table 4.

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Long-Term Effects

Only one study by Roos et al. (2014) assessed long-term effects after the exercise intervention. The long-term effects were measured at Month 12 (6 months after the intervention). Changes in the control group and intervention group on 6MWT, RHR, SBP, and DBP were reported.

After 12 months, the control group showed no changes in RHR (77.17 [10.69] bpm to 77.55 [7.90] bpm, p > .05), and a decrease in the walking distance in the 6MWT (547.82 [56.84] m to 545.56 [31.30] m, p > .05), SBP (120, 11 [12.83] mm Hg to 78.21 [8.68] mm Hg, p > .05), and DBP (118.4 [9.66] mm Hg to 77.27 [7.45] mm Hg, p > .05) was described.

In the intervention group, an increase from baseline (540.69 [71.61] m) to Month 12 (552.4 [66.88] m, p > .05) in the 6MWT and a decrease in RHR (80.79 [11.60] bpm to 79, 61 [9] bpm, p > .05), SBP (121.29 [10.50] mm Hg to 118.77 [11.08] mm Hg, p > .05), and DBP (79.36 [8.10] mm Hg to 78.31 [6.93] mm Hg, p > .05) were described.

No significant differences were found between the control and intervention groups from baseline to Month 12 for 6MWT, RHR, SBP, or DBP. At Month 12, differences were found between the control group and intervention group for the distance walked during the 6MWT (545.56 [31.30] m vs. 552.4 [66.88] m, p = .01). No significant differences for RHR (p = .29), DBP (p = .14) or SBP (p = .26) were found between the control and intervention groups at Month 12.

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Discussion

This is, to the best of our knowledge, the first meta-analysis of RCTs evaluating the effects of exercise on 6MWT, RHR, and Wmax in PLWH and follow-up data. A total of 27 studies investigating cardiovascular parameters were included in our meta-analysis. A total of 52 meta-analyses were conducted: seven main meta-analyses and 45 subgroup analyses of different training methods, professional supervision, training frequency, training intensity, control groups without low exercise, and high-quality studies.

The results of the main meta-analysis for VO2max showed a medium increase in SMD (0.66; p < .0001), I 2 = 53%, and a moderate heterogeneity I 2 = 53%. The subgroup analysis for AERT showed a higher SMD (0.73; p < .0001) than in the main analysis and an I 2 of 31%.

The combination of AE and RT entails the use of upper and lower extremity major muscle groups during exercise and an increase in training duration that, in turn, increased cardiorespiratory fitness, granting PLWH a protective factor against comorbidities related to age or HIV infection. The benefits of the combined training (healthier body composition, improved upper and lower body strength, and aerobic power; Fu & Levine, 2013) might affect the quality of life in PLWH (Gomes-Neto et al., 2015) because these physiological changes would allow PLWH to resume or keep up with daily life activities and thus avoid disability.

The improvement in cardiorespiratory fitness was in accordance with other meta-analyses. Gomes-Neto et al. (2015) also found an improvement inVO2Peak (4.48 ml·kg−1·min−1) compared with the control group for AERT on PLWH. O'Brien et al. (2016) found a greater improvement in VO2max in favor of the AERT intervention group versus the control group and a higher VO2max change in AERT intervention (3.71 ml·kg−1·min−1) than for AE intervention alone (2.4–63 ml·kg−1·min−1).

In accordance with the recommendations to prevent cardiovascular disease (Piepoli et al., 2016) and improve health and well-being (Ferguson, 2014) through exercise, performing 150 minutes of exercise or more per week had a positive effect on VO2max in PLWH. Moreover, when comparing PLWH who performed exercise versus participants who were not performing any kind of exercise, there was a higher effect of exercise on VO2max (overall SMD = 0.66 vs. control groups without low exercise SMD = 0.72), in part because changes could also be seen on VO2max after participating in low-dose exercise (Schuch et al., 2016) such as brisk walking (Buyukyazi et al., 2017). The results of VO2max need to be carefully interpreted because the baseline values were not always similar (Schuch et al., 2016).

Of importance in this review is that the clinical test, 6MWT, was able to determine improvement in cardiorespiratory fitness in PLWH. Although only four studies evaluated the distance achieved during the 6MWT, this finding advocates for the feasibility of the 6MWT in PLWH, providing an alternative to the gold standard for evaluating aerobic capacity by means of progressive exercise tests and breath-by-breath gas analysis that requires special laboratory settings, specialized equipment, resources, and staff for testing.

No significant effects were found for HRmax (SMD = −0.38; p = .43) and RHR (SMD = −0.29; p = .32), and a moderate to high heterogeneity (I 2 = 84% and 66%, respectively) on maximal and RHRs was found. In contrast, the subgroup analysis of RHR for AERT showed a significantly high effect size (SMD = −0.91; p = .006), suggesting that the combination of training modalities contributed to lower RHR in PLWH. These data suggest that both types of training interventions (AE + AERT) have a positive effect on lowering heart rate. O'Brien et al. (2016) also found a decline in HRmax (SMD = −7.33 bpm [I 2 = 97%], p < .00001) for the AE plus AERT analysis, a result that partially agreed with our findings.

Although in this meta-analysis only five studies investigated HRmax and four looked at RHR, the changes to these outcome parameters were in accordance with long-term adaptations to exercise. A reduced sympathetic activity and enhanced parasympathetic (vagal) activity of the autonomic nervous system and a decline in the intrinsic heart rate were the principal physiological changes reducing RHR. A decrease in HRmax was attributed to the changes in the autonomic nervous system and an increase in left ventricular filling time with an optimized maximal stroke volume and cardiac output, reflecting better cardiac function in response to exercise and thus an increased work rate (SMD = 0.80; p = .009; I 2 = 14%), allowing PLWH to perform daily life activities without fatigue (Fu & Levine, 2013 ; Rivera-Brown & Frontera, 2012).

Small and non–significant effect sizes were found for SBP and DBP (SBP SMD = −0.27, p = .09; DBP SMD = −0.01, p = .89) with a moderate to very low I 2 of 63% and 20%, respectively. The subgroup analysis for AE showed a high non–significant effect size (SMD = −0.90; I 2 = 90%; p = .18) on SBP.

Because a limited number of studies in our meta-analysis investigated blood pressure parameters (n = 12), we were unable to find the same significant benefits for PLWH, as reported for normal blood pressure populations, or populations at risk of or living with hypertension (Cornelissen & Smart, 2013). A reduction greater than 5 mm Hg in DBP (Law, Morris, & Wald, 2009) was found in PLWH.

To our knowledge, this is the first meta-analysis that included a relatively high number of studies to report positive changes in heart rate parameters and cardiorespiratory fitness in PLWH. Highlighting the benefits of exercise to cardiovascular markers widely known as modifiable risk factors for cardiovascular disease in general can be a protective factor for PLWH dealing with multiple comorbidities.

The 6MWT is an alternative to the more complex and expensive cardiopulmonary exercise test, where VO2max can be measured directly or estimated from the maximal work performed (Salzman, 2009). Based on our results, the 6MWT was able to objectively assess functional exercise capacity differences after exercise interventions for PLWH. This test is a time- and cost-effective alternative for assessing the functional exercise capacity in PLWH.

Furthermore, as exercise improves the functional exercise capacity of PLWH, it exerts an effect on blood pressure, changes that benefit the population at risk of or with hypertension, and RHR, known to be an independent predictor of cardiovascular and all-cause mortality (Zhang, Wang, & Li, 2016).

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Limitations

In general, the results of our meta-analysis need to be interpreted carefully. Schuch et al. (2016) indicated that the different effect sizes depended on the chosen analysis method. Effect sizes based on the mean change in baseline value can be different from effect sizes resulting only from endpoint measurements. In our meta-analysis, the data were analyzed through endpoint measurements.

Most of the studies included participants of both genders. Some studies that investigated both genders did not mention the percentage of women, so exact statements on gender-specific results cannot be made. Subgroup analyses of studies investigating only populations of men or women are needed.

Nine of the 27 included studies showed a high risk of bias. Although subgroup analyses of high-quality studies were conducted, studies with a high risk of bias limit the value of the results in general.

A potential limitation of our study was that about half of the studies were conducted in the United States, and low- and middle-income countries were underrepresented. Therefore, some attention is needed about extrapolating the results to other cultures with different access to health services and socioeconomic contexts.

Participants from 14 of the 27 included studies had HIV and comorbidities as described by participants' characteristics. The partial or full inclusion of participants with comorbidities and additional medication intake to treat comorbidities may affect the results of the meta-analyses and needs to be taken into account when interpreting the results.

Because of equal dropout rates in the intervention and control groups in the trials, the migration bias within the studies of participants who dropped out was minimized. Also, most of the included studies had relatively small samples. The number of investigated participants in the intervention and control groups was relatively equal at baseline and postmeasurement, so the risk of a sample bias within the studies was minimized. The number of participants in the included studies varied greatly, from 11 to 80 participants. This increased the risk of a sample bias among the studies and could lead to high statistical heterogeneity in the meta-analyses. Further studies with a lower withdrawal rate and a higher number of participants are needed to minimize migration and sample size biases as well.

It is known that ART affects physiological parameters such as muscle tissue, body composition, and cardiovascular parameters. As described in the participants' characteristics, 17 studies mentioned ART. Although medication intake among participants in the studies was similar, the risk of medication bias was increased among the studies because different types of ART were analyzed through meta-analysis. Also, the duration of ART intake and the number of therapy changes may be different for every participant. These circumstances may influence the effect of any of the investigated exercise methods. Further research with a more homogenous classification for medication intake and duration is needed.

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Implications for Research

During the review of the included studies, several key points concerning implications for further research were revealed. First, many criteria of the PEDro scale for quality assessment were fulfilled by only a few studies: blinding the subject (Criterion IV) in 26 studies and blinding the researcher/evaluator (Criterion V) in 26 studies. Criterion VIII (intention to treat) was not fulfilled by 19 studies. Investigators of further HIV and exercise studies need to consider the quality assessment criteria mentioned above that were not addressed. Because several subgroup analyses were based on small sample sizes and a small number of trials, the results need to be interpreted carefully and more studies, especially high-quality studies, are needed for further meta-analyses. Effect sizes based on the mean change (baseline to endpoint; Schuch et al., 2016) need to be conducted to compare the results of endpoint meta-analyses. Furthermore, studies investigating alternative exercises such as yoga (Agarwal, Kumar, & Lewis, 2015 ; Naoroibam, Metri, Bhargav, Nagaratna, & Nagendra, 2016) and tai chi (McCain et al., 2008) did not assess cardiovascular outcomes. Studies assessing alternative exercise methods need to include an investigation of cardiovascular parameters even if the focus relies more on psychological outcomes.

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Conclusion

Our meta-analysis showed that AERT had a greater effect size compared with AE alone on maximal oxygen consumption; the effects were also higher for people who exercised at least three sessions/week and for at least 150 min/week. Combined exercise should be prescribed to promote the physical health of PLWH.

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Key Considerations

  • Aerobic exercise combined with RT is safe and significantly improves maximal oxygen consumption in PLWH.
  • Exercise should be performed 150 minutes per week to significantly improve the 6MWT and Wmax.
  • Aerobic exercise combined with RT improves the RHR.
  • Exercise has no effect on the SBP and DBP and HRmax.
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Disclosures

The authors report no real or perceived vested interest that relates to this article that could be construed as a conflict of interest.

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Acknowledgments

The study was partly funded by an intramural junior research group grant to Andreas Heissel, PhD, at the University of Potsdam. Philipp Zech, Dipl, was partly funded by a scholarship from the FAZIT-Stiftung (Frankfurter Allgemeine Zeitung—FAZ). Camilo Pérez-Chaparro, MD, was funded by the COLFUTURO-DAAD scholarship through his doctoral studies.

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        Keywords:

        aerobic exercise; cardiovascular; HIV; long-term effects; physical exercise; resistance training

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