Physical activity and exercise to improve cardiovascular health for adults living with HIV

Journal Pre-proof Physical activity and exercise to improve cardiovascular health for adults living with HIV

Cemal Ozemek, Kristine M. Erlandson, Catherine M. Jankowski PII:

S0033-0620(20)30027-X

DOI:

https://doi.org/10.1016/j.pcad.2020.01.005

Reference:

YPCAD 1040

To appear in:

Progress in Cardiovascular Diseases

Received date:

29 January 2020

Accepted date:

29 January 2020

Please cite this article as: C. Ozemek, K.M. Erlandson and C.M. Jankowski, Physical activity and exercise to improve cardiovascular health for adults living with HIV, Progress in Cardiovascular Diseases(2020), https://doi.org/10.1016/j.pcad.2020.01.005

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© 2020 Published by Elsevier.

Journal Pre-proof Physical Activity and Exercise to Improve Cardiovascular Health for Adults Living with HIV Cemal Ozemek (1), Kristine M. Erlandson (2) and Catherine M. Jankowski (3)

(1) Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA

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(2) School of Medicine, Division of Infectious Diseases, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA

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(3) College of Nursing, University of Colorado, Aurora, Colorado, USA

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Conflicts of interest: KME has received payments for consulting from ViiV and Gilead Sciences and grant funding from Gilead Sciences (paid to the University of Colorado).

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Address Correspondence to: Cemal Ozemek, PhD, FACSM, ACSM-CEP, RCEP Director, Cardiac Rehabilitation Clinical Assistant Professor Department of Physical Therapy University of Illinois at Chicago 1640 W Roosevelt Rd., 308A (MC 887) Chicago, IL 60608 [email protected]

Journal Pre-proof List of Abbreviations: AIDS – acquired immunodeficiency syndrome ACTG – AIDS Clinical Trials Group ART – antiretroviral therapy CRF – cardiorespiratory fitness CV – cardiovascular

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CVD – cardiovascular disease

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HDL – high-density lipoprotein

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HF – heart failure

LDL – low-density lipoprotein

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INSTI – integrase strand transfer inhibitors

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HIV – human immunodeficiency virus

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NRTI – nucleoside/tide reverse transcriptase inhibitors

PI – protease inhibitors

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PA – Physical Activity

TG – triglyceride

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PLWH – people living with human immunodeficiency virus

VO2peak – peak oxygen consumption WC – waist circumference

Journal Pre-proof Abstract Pharmacologic advancements in the treatment of human immunodeficiency virus (HIV) has extended the life expectancy of people living with HIV (PLWH). An unfortunate side effect of HIV treatment, however, is an increased prevalence of dyslipidemia, glycemic dysregulation and abnormal distribution of body fat (lipodystrophy). Consequently, the risk of developing cardiovascular disease (CVD) is significantly increased in PLWH and ultimately a major cause

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of mortality. Physical activity and exercise training are interventions that have effectively

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protected against the development of CVD and, in the presence of CVD, has help mitigate

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morbidity and mortality. Early concerns over potential immunosuppressive effects of exercise in

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PLWH have largely been dispelled and in some cases exercise has been shown to strengthen markers of immune function. Interventions with aerobic exercise, resistance exercise, and their

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combination, particularly at higher intensities, are showing promising health outcomes in PLWH.

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This review will summarize the key cardiovascular and metabolic effects of antiretroviral therapy; the effects of the types and intensities of exercise on cardiorespiratory fitness,

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cardiometabolic markers, and muscle strength; and provide recommendations on strategies to

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apply exercise interventions in clinical settings.

Key Words: HIV, physical activity, exercise, cardiovascular disease

Journal Pre-proof The number of people living with human immunodeficiency virus (PLWH) has steadily increased largely due to early detection, treatment, and advancements in antiretroviral therapy (ART). Although ART has contributed to a drastic increase in life expectancy, the side effects of years of ART may contribute to the development of multimorbidity, including metabolic diseases and cardiovascular (CV) disease (CVD). Accordingly, over one-half of deaths in PLWH are now related to non-HIV causes1, with one of the leading and continuously rising causes of

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mortality being CVD2. Furthermore, the increased life expectancy of PLWH is now increasing

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the number of older PLWH3. In addition to age-related decrements in physical function, HIV and

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increasing the likelihood of becoming frail4.

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its treatment may contribute to an acceleration or accentuation of the aging process, thus

The increased risk of developing CVD in PLWH is not completely understood, however,

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a combination of direct HIV effects and the associated dyslipidemia caused by ART, increased

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inflammation, irregular coagulation, and monocyte activation have been identified as major contributors5. Additionally, PLWH are less likely to receive aspirin, antiplatelet therapy, statin

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therapy, and smoking cessation advice compared to individuals without HIV6. Collectively, these

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factors impair CV, skeletal muscle, and metabolic function and thereby impair cardiorespiratory fitness (CRF), a telling prognostic measure7. Regular physical activity (PA) and exercise training increase CRF across populations. Furthermore, there is increasing evidence of the beneficial effects of regular exercise on cardiometabolic biomarkers, CRF, muscle strength, immune function, and body composition (Table 1) in PLWH. This review aims to summarize the cardiometabolic consequences of ART and the effects of PA and exercise on CRF, cardiometabolic factors, muscle strength and body composition in PLWH.

Journal Pre-proof Treatment of HIV and Cardiometabolic Consequences The cardiometabolic toxicities of ART are well recognized and have played a major role in alterations in ART treatment guidelines over the past three decades of ART availability. With toxicity of some older therapies, including development of profound lipodystrophy, diabetes, and marked lipid abnormalities8, earlier treatment guidelines recommended delayed initiation of ART until the development of opportunistic infections or CD4+ T-cell counts <200 cells/uL, or

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removed patients from therapy intermittently to limit long-term toxicity. Indeed, many of these

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earlier, toxic therapies are no longer available (i.e., amprenavir, zalcitabine) or are only rarely

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used (i.e., zidovudine, didanosine), as newer, safer ART regimens have been approved. In

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addition to the metabolic effects, lipodystrophy was thought to also impair CRF as a result of fatty infiltration of skeletal muscle, associated with increased inflammation, impairments in

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mitochondrial function and reduced oxidative capacity9. However, untreated HIV and advanced

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HIV on ART were also thought to result in increased intramyocardial lipid infiltration and impaired diastolic function 10, subsequently decreasing CRF, and increasing the risk of

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developing heart failure (HF)11.

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The questions surrounding risk of ART versus risk of HIV progression led to the landmark Strategies for Management of Anti-Retroviral Therapy Study of intermittent ART versus continuous therapy, providing clear evidence as to the benefits of continuous therapy on reducing both acquired immunodeficiency syndrome (AIDS) and non-AIDS mortality. In contrast to the hypothesized toxicity associated with ongoing ART, there was instead a reduction in CV events, mediated in part through a reduction in inflammation12, 13. The combination of safer therapies and benefits of earlier treatment, including reduced transmission to persons without HIV, have culminated in the current recommendations for ART initiation as early as

Journal Pre-proof possible. As a result, many persons living with HIV will initiate ART with minimal immune compromise and without the wasting that many of their predecessors experienced, but will ultimately have decades of subsequent exposure to ART. While the currently approved and recommended ART agents are markedly safer than those in the initial AIDS epidemic, concern for cardiometabolic toxicities persists. First-generation nucleoside/tide reverse transcriptase inhibitors (NRTIs; stavudine, zidovudine) and the protease

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inhibitors (PI) are the most recognized classes for the detrimental effects on lipids and glucose

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and the propensity to cause changes in body fat distribution (lipodystrophy)14-16. Confounding

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the effect of PIs is the need for a pharmacologic boosting agent, either ritonavir or cobicistat, to

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achieve adequate drug levels. Similar to the PIs, these additional agents have also been associated with lipid effects and a heightened risk of drug-drug interactions with concomitant

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medications including statins17. The extent to which PIs directly contribute to heightened

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cardiometabolic risk can be challenging to tease out in cohort data and meta-analyses. Among PLWH hospitalized with HF, use of PI was associated with higher CV mortality and 30-day HF

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readmission18. In the observational Data Collection on Adverse Events of Anti-HIV Drugs study,

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among participants taking contemporary PIs, an increased CVD risk was seen among participants taking ritonavir-boosted darunavir, but not atazanavir19. As PIs have a high genetic barrier for resistance they were often the preferred therapy for less adherent patient populations, thus a higher CVD risk may be confounded by additional risks for CVD events (such as substance abuse)20, 21. As such, randomized clinical trial data can provide unbiased insights. In the AIDS Clinical Trials Group (ACTG) A5224s, the PI boosted atazanavir had similar cardiometabolic effects as a comparator NNRTI, efavirenz22, and significantly less effect on fasting serum glucose23. A subsequent AIDS Clinical Trials Group Study (A5257)

Journal Pre-proof randomized ART-naïve individuals to one of two boosted PIs (darunavir or atazanavir, both with ritonavir), or raltegravir, first in the new class of integrase strand transfer inhibitors (INSTI), all with the same backbone therapy24. Both PIs and the INSTI were associated with significant increases in fat depots with no between-arm differences, no differences in insulin resistance25, similar increases in lipids by PI26, but significantly less progression of carotid intima medial thickness among those randomized to boosted atazanavir than to darunavir or raltegravir26. The

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safer CVD risk profile of atazanavir may possibly be explained by elevations in bilirubin27. In

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summary, PIs are highly potent HIV medications that have saved millions of lives and continue

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to do so, despite these toxicities. Of the PIs, atazanavir appears to have the safest CV profile,

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however, concerns for toxicity and drug-drug interactions have shifted preferred therapies away from the PI class.

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Teasing out PI-associated toxicity can be challenging when therapy is most commonly

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prescribed with a backbone of two NRTIs. The most commonly prescribed backbone therapies include abacavir or tenofovir disoproxil fumarate, now often replaced by the newer tenofovir

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alafenamide. In multiple cohort treatment studies, abacavir has been associated with increased

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CVD risk28-32; smaller treatment studies have suggested that this risk may be mediated through platelet adhesion factors. These risks are reflected in ART treatment guidelines, which recommend avoiding abacavir among patients with a high CVD risk. The development and approval of the newer NRTI tenofovir alafenamide has been met with a worsening lipid profile33, 34

and early evidence suggesting a markedly greater weight gain35, 36. Other ART classes

including NNRTIs (efavirenz, nevirapine) and entry inhibitors (maraviroc) have not been consistently implicated in CVD risk32, 37.

Journal Pre-proof The first INSTI, raltegravir, was approved by the Food and Drug Administration in 2007, with the expectations of a safer alternative to the PIs. Indeed, many studies demonstrated a beneficial effect on lipids, markers of glucose metabolism38-41, and hepatic steatosis, albeit without a beneficial effect on visceral adiposity. Three additional INSTIs have been approved: elvitegravir which, similar to the PIs, requires use of a boosting agent, dolutegravir (available singly or in fixed-dose combination with abacavir and lamivudine), and bictegravir (available

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only in fixed dose combination with tenofovir alafenamide and emtricitabine). Most recently,

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more than 10 years after the initial approval of the INSTIs, randomized controlled trials, cohort

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studies, and clinical data now suggest significantly and often markedly greater weight gain with

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the initiation of or switch to INSTIs35, 42-46, especially in combination with tenofovir alafenamide and in certain populations (women, blacks). The underlying mechanisms of this weight gain are

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likely multifactorial, and confounded by the overall increase in body weight in PLWH,

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especially at the time of ART initiation35, 47-49. In summary, the development of safer ART and studies demonstrating the benefits of viral suppression have resulted in early initiation and long-

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term, consistent treatment of ART. Although newer therapies are infrequently associated with

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lipodystrophy, some agents are still linked to an increased risk of CVD. Furthermore, first-line agents are associated with a newly recognized risk of weight gain. If this weight gain continues well past the switch or initiation period, the clinical implications with years of ART may be profound. Interventions to prevent and reverse ART-related metabolic consequences are urgently needed.

Physical Activity and Exercise Despite the cardiometabolic consequences of HIV and ART, PA appears to modulate the health profile of PLWH. In the general population, an accumulation of data supports the

Journal Pre-proof multisystemic benefits of aerobic exercise across the lifespan, such that those engaging in regular aerobic exercise often experience improvements and/or preservation of glycemic regulation, CV function, maintenance of skeletal muscle quality and quantity, blood pressure management, normalization of cholesterol levels, reduced stress and improved quality of life50-52. Similarly, physically active PLWH have significantly lower advanced glycation end products, lower triglycerides (TG), waist circumference (WC)53, and less lipodystrophy than non-active PLWH54.

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In an attempt to better understand the extent to which aerobic exercise can improve clinically

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meaningful and HIV relevant markers, it is important to appreciate the existing heterogeneity

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among exercise intervention studies.

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Aerobic Exercise

It is generally accepted that progressive exercise volumes (product of intensity, duration

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and frequency of activity), to a certain extent, can contribute to greater improvements in

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physiologic markers55. Studies implementing low volume (shorter duration and frequency) aerobic exercise interventions have generally led to non-significant changes in CRF due to an

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insufficient stimulus56. Numerous studies have identified similar or superior effects of vigorous

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intensity exercise in enhancing CRF, body composition, skeletal muscle quantity and quality in healthy populations and populations with comorbidities55, 57. Among adult PLWH, Stringer and colleagues randomized participants to a control group, moderate intensity (80% of lactate threshold, 3 days per week for 60 minutes) or high intensity (50% of the difference between peak volume of oxygen consumption (VO2peak) and lactate threshold, 3 days per week for 30-40 minutes) exercise for 6 weeks58. Higher intensity exercise contributed to a 13% increase in VO2peak, whereas both control and moderate intensity exercise groups remained the same. Early work by Smith et al., found that performing moderate to vigorous aerobic exercise contributes to

Journal Pre-proof significant decreases in fatigue, body weight, and WC59. Similar outcomes have also been reported in PLWH ≥50 years old, a population at greater CVD risk: moderate continuous or interval aerobic exercise increased CRF, as assessed by VO2peak, by 2.63 ml/kg/min 60, whereas high intensity exercise has been shown to increase VO2peak by 4.7±3.9 ml/kg/min61. Oursler and colleagues62 reported a significantly (p<0.01) greater increase in CRF (3.6±1.2 ml/kg/min, p=0.02) in PLWH that performed 16 weeks of vigorous-intensity exercise

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that progressed to 40-45 minutes at 75-90% of heart rate reserve compared to minimal change in

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CRF (0.4±1.4 ml/kg/min, p=0.07) among participants performing up to 45 minutes of walking at

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a self-selected moderate pace. However, despite the significant improvements in CRF, measures

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of body composition and lipid levels were unchanged between the groups. Resistance Exercise

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The few studies of resistance exercise in PLWH published after 2007 (aligning with

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newer ART regimens) have small sample sizes (e.g., N ≤ 30) and only about half are randomized trials with a control group. Limitations aside, there is mounting evidence that resistance exercise

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training elicits beneficial changes in muscle strength, body composition, CVD risk factors,

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inflammation, and immune activation in PLWH. In two small RCTs with resistance exercise interventions of 12 weeks, upper and lower body strength increased, subcutaneous fat decreased, and peripheral blood CD4+ and CD8+ T-cell counts increased 63, 64 compared to non-exercising controls. Other significant changes included a reduced WC63 increased lean mass percentage63, 64, and reduced levels of circulating pro-inflammatory cytokines (IL-1ß, IL-6, IL-8, and IL-10; TNFα, C-reactive protein)63, 65. Additionally, total cholesterol, TG, and low-density lipoprotein (LDL) decreased significantly while high-density lipoprotein (HDL) increased with resistance exercise65. The participants in these studies were 40 years of age on average, were well-

Journal Pre-proof controlled on ART, inexperienced with resistance exercise, and there was an approximately equal representation of women and men63-65. Among PLWH who also had metabolic syndrome, resistance exercise training for 12 weeks66 resulted in significant decreases in fasting glucose, hemoglobin A1C, WC and body fat percentage, and increased HDL compared to controls. After the intervention, the exercisers (n=10 of 21 participants) no longer had metabolic syndrome. In a 6-week resistance training

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intervention during inpatient substance abuse recovery67, muscle mass and strength increased

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significantly in young men with HIV compared to non-exercising controls. There were no

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changes in pro-inflammatory cytokines in response to training, which may be attributed to the

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shorter duration of training and the confounding effects of substance abuse. However, the environmental conditions, including diet, were controlled in this inpatient study.

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Some of the favorable adaptations to resistance exercise training found in middle-aged

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PLWH are also present in older, medically complex PLWH. In a one-year intervention68 comparing PLWH to uninfected controls, mean age 65 years, 10 of the 11 PLWH on ART, 6 had

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AIDS-defining symptoms, and the use of medications for comorbidities (e.g., beta-blockers,

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statins) was common. When compared to the HIV-uninfected exercisers, PLWH had less upper body and leg strength at baseline (pre-training) and greater gains in strength with training, but leg strength remained significantly lower than controls after training. Fasting blood sugar decreased significantly with training in the older PLWH, but blood lipids were unchanged. In the RCTs described above, weight machines or free weights provided the exercise stimulus. However, in an 8-week intervention using elastic resistance bands and body weight exercises69, CD4+ T-cell count and lean body mass increased significantly in PLWH, and fat mass and WC decreased compared to non-exercisers. This study, although small (N=18; 33%

Journal Pre-proof women), is important because it demonstrates the feasibility of implementing effective resistance exercise training for PLWH when resources (e.g., equipment, space) are limited. In two small, nonrandomized studies of middle-aged PLWH, resting heart rate decreased significantly70 and bone mineral density of the lumbar spine, femoral neck, and radius increased significantly71 in response to 12-week resistance interventions (36 sessions progressing to 8 repetitions at 70-80% of one repetition max for 8 upper and lower extremity exercises). Muscle

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because they had a confirmed history of low bone density.

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strength increased in both studies and, in Santos et al71, the participants (N=20) were selected

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Finally, other health benefits of resistance exercise for PLWH have been studied in single-bout studies. In a pilot study72 of black PLWH (N=42), depressive symptoms improved

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more after a bout of moderate- than high-intensity resistance exercise. In a pilot study73 of blood

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pressure responses during and after one bout of resistance exercise in women with HIV (N=12),

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clinically relevant decreases (≥ 4 mm) in systolic blood pressure were seen in women with a greater waist-to-hip circumference ratio, and decreases in diastolic pressure in those who had

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used ART for a shorter time. These promising preliminary results require confirmation in larger

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studies. Whether these acute responses will translate to sustained improvements with regular resistance exercise remains to be determined. It is not surprising that resistance exercise training increases muscle strength in PLWH because the musculoskeletal system is exposed to a very specific stimulus. While strength alone is a beneficial adaptation for daily life, particularly for frailty prevention in middle-aged and older adults, other adaptations imparted by resistance exercise can improve the health of PLWH and offset some of the longer term consequences of prolonged ART. Combined Exercise

Journal Pre-proof Aerobic and resistance exercise interventions have independently demonstrated efficacy in improving many components of health. When performed together, one may acquire benefits that protect the CV system, increase muscular strength, and reduce the presence of common risk factors of frailty and falls. This may be especially true and clinically relevant among older PLWH who experience both CV and skeletal muscle impairments. Combined aerobic and progressive resistance exercise interventions have been shown to

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significantly increase CRF and lean body mass, and decrease body fat percentage and strength60.

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Recently, Erlandson et al. implemented a 24-week aerobic and strength training intervention that

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progressed participants from an initial low intensity familiarization period (2 weeks), followed

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by 10 weeks of moderate intensity exercise. Participants were then randomized to undergo either 12 additional weeks of moderate intensity exercise (40-50% VO2peak, 60-70% of 1RM) or high

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intensity exercise (60-70% VO2peak, >80% 1RM). Both moderate and high intensity groups

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were found to significantly improve CRF, physical function, and strength, and decrease total body fat74. Others have shown a potential additive benefit of statin therapy: Zanetti and

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colleagues compared the effects of combined aerobic and strength exercise with statin therapy vs

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exercise alone, statin alone, or placebo75. Both exercise groups increased CRF and measures of muscular strength compared to no change in the statin and placebo conditions. Individuals in the combined exercise and statin treatment group experienced significantly greater improvements in total cholesterol, TG and interleukin-8 levels; both exercise groups experienced increased lean body mass and decreased percent body fat. Coupling exercise with pharmacologic interventions aimed at attenuating CVD risk factors presents a compelling approach to achieve additional health benefits beyond exercise alone.

Journal Pre-proof Promoting Physical Activity Despite the widely recognized and promoted health benefits of a physically active lifestyle76, negligible improvements in the number of individuals meeting the National PA Guidelines has been seen over the past 50 years77, 78. The proportion of PLWH meeting the aerobic (i.e., CV) component of the PA recommendations (≥150 minutes of moderate PA or 75 minutes of vigorous PA or an equivalent combination of the two) is discouraging, with only

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48.8% (95% confidence interval, 37.2-60.7%) meeting the aerobic component by self-report79

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and only 30% meeting recommendations when assessed via accelerometry80. To our knowledge,

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the number of PLWH meeting both aerobic and resistance components of the PA guidelines is

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not known. As only 24% of U.S. adults meet both components of the guidelines81, we expect that a similarly small percentage of PLWH meet both aerobic and resistance activities.

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In a large systematic review, similar to the general public, higher education levels and

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annual income, and manual labor occupation were associated with higher PA levels within PLWH54. Furthermore, individuals with a positive health attitude and higher self-efficacy tended

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to be more physically active, whereas lower PA levels were found in those experiencing

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depressive symptoms and greater bodily pain54. Understanding the associations of biological, behavioral, and psychosocial factors with PA can help inform effective exercise engagement strategies to improve PA.

Clinical Application of Exercise Interventions The benefits of exercise interventions discussed in this review highlight the need to facilitate the implementation of exercise interventions in clinical settings for PLWH. Clinicians must first recognize barriers within their practice that limit the ability to educate, promote and

Journal Pre-proof foster exercise adoption. An assessment of PA and its endorsement must be integrated into clinical visits. The two-item PA Vital Sign questionnaire has good agreement with objective measures of PA with 2 simple questions: 1) how many days in a week is moderate-to-vigorous PA is performed; and 2) how many minutes are spent in those intensities82, 83. As a screening tool, this can be used to initiate a conversation about PA and exercise. Integrating measures of CRF and physical function can identify individuals with the greatest need for exercise

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interventions and for clinical programs such as cardiac or physical rehabilitation. Intensive

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cardiopulmonary exercise testing may not be feasible, but less intensive tests such as a 6 minute

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walk test (6MWT) or 400 meter walk test correlate with more intensive measures of CRF84 85.

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Due to the low level of PA in most PLWH, a greater level of interaction may be required to advise, initiate and maintain exercise recommendations. Multidisciplinary teams that consist

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of clinical exercise physiologists, physical therapists and nurses have been a particularly

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effective strategy to promote exercise in populations with CVD86, 87. By having the ability to dedicate a greater volume of time identifying patient risk factors, barriers and preferences for

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exercise, the allied health professionals can direct patients towards appropriate exercise programs

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or create a plan for home-based exercise. Limited data suggest the efficacy of home-based exercise programs may be similar to supervised programs60, and mobile health applications appear to improve VO2 peak, fat and fat-free mass%, total-, LDL-cholesterol and TG, depressive symptoms and mood88. More research is needed in this area to confirm the efficacy of mobile health applications across health status in PLWH. As dietary intervention is associated with greater weight loss than exercise alone, guidance for healthy eating or nutritionist-guided dietary intervention in addition to an exercise regimen for individuals on or starting ART may be a

Journal Pre-proof reasonable strategy to facilitate weight loss and improve cardiometabolic health. For further information on this topic, readers are referred to recent reviews15, 89, 90.

Conclusion Advances in ART and treatment strategies have drastically extended life expectancy yet PLWH are now aging with a growing burden of CVD and other metabolic disturbances,

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including a newly appreciated epidemic of obesity. Starting a regular exercise program, or

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maintaining a physically active lifestyle, is associated with favorable metabolic health profiles

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and a lower prevalence of CVD risk factors among PWH. Furthermore, higher-intensity exercise

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appears to result in even greater health benefits without exacerbation of underlying immune dysfunction. With the mounting evidence supporting the positive effects of combined aerobic

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and strength exercise, efforts must now be made to optimize the translation of investigative

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options for all PLWH.

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findings into clinical settings and make exercise programs available, feasible, and maintainable

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Strength

↑a

↔a

Strength

Body weight

Lean Mass

Fat Mass

QOL

-

↔a ↔a

↑a ↑a

↔a ↔a

↑a ↑a

↑ a, c

↑a

↔a

↔a

↑a

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Table 1. Effects of exercise training in PLWH CD4 Study Peak VO2 Count Aerobic Continuous ↑a ↔a a,b Interval ↑ ↑a

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Combined ↑a ↔a ↑a ↑a ↑a ↔a 57 Summarized meta-analysis outcomes from O’Brien, BMC Infec Dis 2016 and O’Brien, BMC Infec Dis 201789 a comparison with no exercise intervention. b comparison with continuous aerobic exercise c comparison with aerobic exercise only

↑a

Journal Pre-proof REFERENCES 1.

Antiretroviral Therapy Cohort C. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2010;50:1387-1396.

2.

Feinstein MJ, Bahiru E, Achenbach C, et al. Patterns of Cardiovascular Mortality for

of

HIV-Infected Adults in the United States: 1999 to 2013. Am J Cardiol. 2016;117:214-

Legarth RA, Ahlström MG, Kronborg G, et al. Long-Term Mortality in HIV-Infected

-p

3.

ro

220.

re

Individuals 50 Years or Older: A Nationwide, Population-Based Cohort Study. Journal of acquired immune deficiency syndromes (1999). 2016;71:213-218. Piggott DA, Erlandson KM, Yarasheski KE. Frailty in HIV: Epidemiology, Biology,

lP

4.

2016;13:340-348.

Deeks SG, Tracy R, Douek DC. Systemic effects of inflammation on health during

ur

5.

na

Measurement, Interventions, and Research Needs. Current HIV/AIDS reports.

6.

Jo

chronic HIV infection. Immunity. 2013;39:633-645. Ladapo JA, Richards AK, DeWitt CM, et al. Disparities in the Quality of Cardiovascular Care Between HIV-Infected Versus HIV-Uninfected Adults in the United States: A Cross-Sectional Study. Journal of the American Heart Association. 2017;6:e007107. 7.

Guazzi M, Bandera F, Ozemek C, Systrom D, Arena R. Cardiopulmonary Exercise Testing: What Is its Value? J Am Coll Cardiol. 2017;70:1618-1636.

8.

Agenerase (amprenavir) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.

Journal Pre-proof 9.

Røge BT, Calbet JAL, Møller K, et al. Skeletal muscle mitochondrial function and exercise capacity in HIV-infected patients with lipodystrophy and elevated p-lactate levels. AIDS (London, England). 2002;16:973-982.

10.

Nayak G, Ferguson M, Tribble DR, et al. Cardiac diastolic dysfunction is prevalent in HIV-infected patients. AIDS Patient Care STDS. 2009;23:231-238.

11.

Oursler KK, O'Boyle HM, Briggs BC, et al. Association of Diastolic Dysfunction with

of

Reduced Cardiorespiratory Fitness in Adults Living with HIV. AIDS patient care and

Siedner MJ. START or SMART? Timing of Antiretroviral Therapy Initiation and

-p

12.

ro

STDs. 2019;33:493-499.

Forum Infect Dis. 2016;3:ofw032.

Phillips AN, Carr A, Neuhaus J, et al. Interruption of antiretroviral therapy and risk of

lP

13.

re

Cardiovascular Risk for People With Human Immunodeficiency Virus Infection. Open

na

cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir Ther. 2008;13:177-187. Lagathu C, Bereziat V, Gorwood J, et al. Metabolic complications affecting adipose

ur

14.

Jo

tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment. Expert Opin Drug Saf. 2019;18:829-840. 15.

Lake JE, Stanley TL, Apovian CM, et al. Practical Review of Recognition and Management of Obesity and Lipohypertrophy in Human Immunodeficiency Virus Infection. Clin Infect Dis. 2017;64:1422-1429.

16.

Erlandson KM, Lake JE. Fat Matters: Understanding the Role of Adipose Tissue in Health in HIV Infection. Curr HIV/AIDS Rep. 2016;13:20-30.

Journal Pre-proof 17.

Renjifo B, van Wyk J, Salem AH, Bow D, Ng J, Norton M. Pharmacokinetic enhancement in HIV antiretroviral therapy: a comparison of ritonavir and cobicistat. AIDS Rev. 2015;17:37-46.

18.

Alvi RM, Neilan AM, Tariq N, et al. Protease Inhibitors and Cardiovascular Outcomes in Patients With HIV and Heart Failure. J Am Coll Cardiol. 2018;72:518-530.

19.

Ryom L, Lundgren JD, El-Sadr W, et al. Cardiovascular disease and use of contemporary

of

protease inhibitors: the D:A:D international prospective multicohort study. Lancet HIV.

Bangsberg DR, Acosta EP, Gupta R, et al. Adherence-resistance relationships for

-p

20.

ro

2018;5:e291-e300.

fitness. Aids. 2006;20:223-231.

Walmsley S. Protease inhibitor-based regimens for HIV therapy: safety and efficacy. J

lP

21.

re

protease and non-nucleoside reverse transcriptase inhibitors explained by virological

22.

na

Acquir Immune Defic Syndr. 2007;45 Suppl 1:S5-13; quiz S28-31. McComsey GA, Kitch D, Sax PE, et al. Peripheral and central fat changes in subjects

ur

randomized to abacavir-lamivudine or tenofovir-emtricitabine with atazanavir-ritonavir

23.

Jo

or efavirenz: ACTG Study A5224s. Clin Infect Dis. 2011;53:185-196. Erlandson KM, Kitch D, Tierney C, et al. Impact of randomized antiretroviral therapy initiation on glucose metabolism. Aids. 2014;28:1451-1461. 24.

Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461-471.

Journal Pre-proof 25.

Dirajlal-Fargo S, Moser C, Brown TT, et al. Changes in Insulin Resistance After Initiation of Raltegravir or Protease Inhibitors With Tenofovir-Emtricitabine: AIDS Clinical Trials Group A5260s. Open Forum Infect Dis. 2016;3:ofw174.

26.

Stein JH, Ribaudo HJ, Hodis HN, et al. A prospective, randomized clinical trial of antiretroviral therapies on carotid wall thickness. Aids. 2015;29:1775-1783.

27.

Crane HM, Nance RM, Heckbert SR, et al. Association Between Bilirubin, Atazanavir,

of

and Cardiovascular Disease Events Among People Living With HIV Across the United

Dorjee K, Baxi SM, Reingold AL, Hubbard A. Risk of cardiovascular events from

-p

28.

ro

States. Journal of acquired immune deficiency syndromes (1999). 2019;81:e141-e147.

re

current, recent, and cumulative exposure to abacavir among persons living with HIV who were receiving antiretroviral therapy in the United States: a cohort study. BMC Infect Dis.

Marcus JL, Neugebauer RS, Leyden WA, et al. Use of Abacavir and Risk of

na

29.

lP

2017;17:708.

Cardiovascular Disease Among HIV-Infected Individuals. J Acquir Immune Defic Syndr.

Kovari H, Calmy A, Doco-Lecompte T, et al. Antiretroviral Drugs Associated with

Jo

30.

ur

2016;71:413-419.

Subclinical Coronary Artery Disease in the Swiss HIV Cohort Study. Clin Infect Dis. 2019. 31.

Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. Aids. 2011;25:1289-1298.

Journal Pre-proof 32.

Eyawo O, Brockman G, Goldsmith CH, et al. Risk of myocardial infarction among people living with HIV: an updated systematic review and meta-analysis. BMJ Open. 2019;9:e025874.

33.

Milinkovic A, Berger F, Arenas-Pinto A, Mauss S. Reversible effect on lipids by switching from tenofovir disoproxil fumarate to tenofovir alafenamide and back. Aids. 2019;33:2387-2391. Kauppinen KJ, Kivela P, Sutinen J. Switching from Tenofovir Disoproxil Fumarate to

of

34.

Sax PE, Erlandson KM, Lake JE, et al. Weight Gain Following Initiation of

re

35.

-p

AIDS Patient Care STDS. 2019;33:500-506.

ro

Tenofovir Alafenamide Significantly Worsens the Lipid Profile in a Real-World Setting.

Antiretroviral Therapy: Risk Factors in Randomized Comparative Clinical Trials. Clin

Gomez M, Seybold U, Roider J, Harter G, Bogner JR. A retrospective analysis of weight

na

36.

lP

Infect Dis. 2019.

changes in HIV-positive patients switching from a tenofovir disoproxil fumarate (TDF)-

ur

to a tenofovir alafenamide fumarate (TAF)-containing treatment regimen in one German

37.

Jo

university hospital in 2015-2017. Infection. 2019;47:95-102. Francisci D, Pirro M, Schiaroli E, et al. Maraviroc Intensification Modulates Atherosclerotic Progression in HIV-Suppressed Patients at High Cardiovascular Risk. A Randomized, Crossover Pilot Study. Open Forum Infect Dis. 2019;6:ofz112. 38.

Funderburg NT, Xu D, Playford MP, et al. Treatment of HIV infection with a raltegravirbased regimen increases LDL levels, but improves HDL cholesterol efflux capacity. Antivir Ther. 2017;22:71-75.

Journal Pre-proof 39.

Ofotokun I, Na LH, Landovitz RJ, et al. Comparison of the metabolic effects of ritonavirboosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin Infect Dis. 2015;60:1842-1851.

40.

Macias J, Mancebo M, Merino D, et al. Changes in Liver Steatosis After Switching From Efavirenz to Raltegravir Among Human Immunodeficiency Virus-Infected Patients With Nonalcoholic Fatty Liver Disease. Clin Infect Dis. 2017;65:1012-1019. Calza L, Colangeli V, Borderi M, et al. Improvement in liver steatosis after the switch

of

41.

ro

from a ritonavir-boosted protease inhibitor to raltegravir in HIV-infected patients with

Kerchberger AM, Sheth AN, Angert CD, et al. Weight Gain Associated with Integrase

re

42.

-p

non-alcoholic fatty liver disease. Infect Dis (Lond). 2019;51:593-601.

Stand Transfer Inhibitor Use in Women. Clin Infect Dis. 2019. Kouanfack C, Mpoudi-Etame M, Omgba Bassega P, et al. Dolutegravir-Based or Low-

lP

43.

2019;381:816-826.

Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus Two Different Prodrugs

ur

44.

na

Dose Efavirenz-Based Regimen for the Treatment of HIV-1. N Engl J Med.

45.

Jo

of Tenofovir to Treat HIV. N Engl J Med. 2019;381:803-815. Bourgi K, Rebeiro PF, Turner M, et al. Greater Weight Gain in Treatment Naive Persons Starting Dolutegravir-Based Antiretroviral Therapy. Clin Infect Dis. 2019. 46.

Norwood J, Turner M, Bofill C, et al. Brief Report: Weight Gain in Persons With HIV Switched From Efavirenz-Based to Integrase Strand Transfer Inhibitor-Based Regimens. J Acquir Immune Defic Syndr. 2017;76:527-531.

47.

Wood BR. Do Integrase Inhibitors Cause Weight Gain? Clin Infect Dis. 2019.

Journal Pre-proof 48.

Hill A, Waters L, Pozniak A. Are new antiretroviral treatments increasing the risks of clinical obesity? J Virus Erad. 2019;5:41-43.

49.

Mankal PK, Kotler DP. From wasting to obesity, changes in nutritional concerns in HIV/AIDS. Endocrinol Metab Clin North Am. 2014;43:647-663.

50.

Lavie CJ, Johannsen N, Swift D, et al. Exercise is Medicine - The Importance of Physical Activity, Exercise Training, Cardiorespiratory Fitness and Obesity in the Prevention and

Wisloff U, Lavie CJ. Taking Physical Activity, Exercise, and Fitness to a Higher Level.

ro

51.

of

Treatment of Type 2 Diabetes. Eur Endocrinol. 2014;10:18-22.

Lavie CJ, Ozemek C, Carbone S, Katzmarzyk PT, Blair SN. Sedentary Behavior,

re

52.

-p

Prog Cardiovasc Dis. 2017;60:1-2.

Exercise, and Cardiovascular Health. Circ Res. 2019;124:799-815. Rodrigues KL, Borges JP, Lopes GdO, et al. Influence of Physical Exercise on Advanced

lP

53.

na

Glycation End Products Levels in Patients Living With the Human Immunodeficiency Virus. Frontiers in physiology. 2018;9:1641-1641. Vancampfort D, Mugisha J, Richards J, De Hert M, Probst M, Stubbs B. Physical activity

ur

54.

Jo

correlates in people living with HIV/AIDS: a systematic review of 45 studies. Disabil Rehabil. 2018;40:1618-1629. 55.

Wisløff U, Ellingsen Ø, Kemi OJ. High-intensity interval training to maximize cardiac benefits of exercise training? Exercise and sport sciences reviews. 2009;37:139-146.

56.

Baigis J, Korniewicz DM, Chase G, Butz A, Jacobson D, Wu AW. Effectiveness of a home-based exercise intervention for HIV-infected adults: a randomized trial. J Assoc Nurses AIDS Care. 2002;13:33-45.

Journal Pre-proof 57.

Weston KS, Wisløff U, Coombes JS. High-intensity interval training in patients with lifestyle-induced cardiometabolic disease: a systematic review and meta-analysis. British journal of sports medicine. 2014;48:1227-1234.

58.

Stringer WW, Berezovskaya M, O'Brien WA, Beck CK, Casaburi R. The effect of exercise training on aerobic fitness, immune indices, and quality of life in HIV+ patients. Med Sci Sports Exerc. 1998;30:11-16. Smith BA, Neidig JL, Nickel JT, Mitchell GL, Para MF, Fass RJ. Aerobic exercise:

of

59.

O'Brien KK, Tynan AM, Nixon SA, Glazier RH. Effectiveness of aerobic exercise for

re

60.

-p

infected adults. Aids. 2001;15:693-701.

ro

effects on parameters related to fatigue, dyspnea, weight and body composition in HIV-

adults living with HIV: systematic review and meta-analysis using the Cochrane

Mutimura E, Crowther NJ, Cade TW, Yarasheski KE, Stewart A. Exercise training

na

61.

lP

Collaboration protocol. BMC Infect Dis. 2016;16:182.

reduces central adiposity and improves metabolic indices in HAART-treated HIV-

62.

Jo

2008;24:15-23.

ur

positive subjects in Rwanda: a randomized controlled trial. AIDS Res Hum Retroviruses.

Oursler KK, Sorkin JD, Ryan AS, Katzel LI. A pilot randomized aerobic exercise trial in older HIV-infected men: Insights into strategies for successful aging with HIV. PLoS One. 2018;13:e0198855.

63.

Zanetti HR, Cruz LG, Lourenco CL, Neves Fde F, Silva-Vergara ML, Mendes EL. Nonlinear resistance training reduces inflammatory biomarkers in persons living with HIV: A randomized controlled trial. Eur J Sport Sci. 2016;16:1232-1239.

Journal Pre-proof 64.

de Brito-Neto JG, de Andrade MF, de Almeida VD, et al. Strength training improves body composition, muscle strength and increases CD4+ T lymphocyte levels in people living with HIV/AIDS. Infect Dis Rep. 2019;11:7925.

65.

Zanetti HR, da Cruz LG, Lourenco CL, et al. Nonlinear Resistance Training Enhances the Lipid Profile and Reduces Inflammation Marker in People Living With HIV: A Randomized Clinical Trial. J Phys Act Health. 2016;13:765-770. Zanetti HR, da Cruz LG, Lourenco CL, Neves FF, Silva-Vergara ML, Mendes EL. Does

of

66.

ro

nonlinear resistance training reduce metabolic syndrome in people living with HIV? A

Vingren JL, Curtis JH, Levitt DE, et al. Adding Resistance Training to the Standard of

re

67.

-p

randomized clinical trial. J Sports Med Phys Fitness. 2017;57:678-684.

Care for Inpatient Substance Abuse Treatment in Men With Human Immunodeficiency

lP

Virus Improves Skeletal Muscle Health Without Altering Cytokine Concentrations. J

68.

na

Strength Cond Res. 2018;32:76-82.

Souza PM, Jacob-Filho W, Santarem JM, Zomignan AA, Burattini MN. Effect of

ur

progressive resistance exercise on strength evolution of elderly patients living with HIV

69.

Jo

compared to healthy controls. Clinics (Sao Paulo). 2011;66:261-266. Ghayomzadeh M, SeyedAlinaghi S, Shamsi MM, et al. Effect of 8 Weeks of HospitalBased Resistance Training Program on TCD4+ Cell Count and Anthropometric Characteristic of Patients With HIV in Tehran, Iran: A Randomized Controlled Trial. J Strength Cond Res. 2019;33:1146-1155. 70.

Bessa A, Lopez JC, F DIM, Ferry F, Costa ESG, Martins Dantas EH. Lymphocyte CD4+ cell count, strength improvements, heart rate and body composition of HIV-positive

Journal Pre-proof patients during a 3-month strength training program. J Sports Med Phys Fitness. 2017;57:1051-1056. 71.

Santos WR, Santos WR, Paes PP, et al. Impact of Strength Training on Bone Mineral Density in Patients Infected With HIV Exhibiting Lipodystrophy. J Strength Cond Res. 2015;29:3466-3471.

72.

Nosrat S, Whitworth JW, SantaBarbara NJ, Dunsiger SI, Ciccolo JT. Acute Effects of

of

Resistance-Exercise Intensity in Depressed Black/African Americans Living With HIV:

Domingues WJR, Nogueira VC, de Souza DC, Germano-Soares AH, Ritti-Dias R, Avelar

-p

73.

ro

A Randomized Pilot Study. J Sport Exerc Psychol. 2019:1-10.

re

A. Blood pressure responses after resistance exercise session in women living with human immunodeficiency virus/acquired immunodeficiency syndrome. J Exerc Rehabil.

Jankowski CM, Wilson M, Brown TT, MaWhinney S, Erlandson KM. Blunted increase

na

74.

lP

2018;14:688-693.

in muscle mass after exercise training in people aging with HIV. International Workshop

Zanetti HR, Gonçalves A, Teixeira Paranhos Lopes L, et al. Effects of Exercise Training

Jo

75.

ur

HIV/Aging. New York City, New York2019.

and Statin Use in People Living with Human Immunodeficiency Virus with Dyslipidemia. Medicine and science in sports and exercise. 2020;52:16-24. 76.

Piercy KL, Troiano RP. Physical Activity Guidelines for Americans From the US Department of Health and Human Services. Circ Cardiovasc Qual Outcomes. 2018;11:e005263.

77.

Ozemek C, Lavie CJ, Rognmo O. Global physical activity levels - Need for intervention. Prog Cardiovasc Dis. 2019;62:102-107.

Journal Pre-proof 78.

Katzmarzyk PT, Lee IM, Martin CK, Blair SN. Epidemiology of Physical Activity and Exercise Training in the United States. Prog Cardiovasc Dis. 2017;60:3-10.

79.

Vancampfort D, Mugisha J, De Hert M, et al. Global physical activity levels among people living with HIV: a systematic review and meta-analysis. Disabil Rehabil. 2018;40:388-397.

80.

Fillipas S, Cicuttini F, Holland AE, Cherry CL. The international physical activity

of

questionnaire overestimates moderate and vigorous physical activity in HIV-infected

Schiller JSC, T.C.; Norris, T. Early release of selected estimates based on data from the

-p

81.

ro

individuals compared with accelerometry. J Assoc Nurses AIDS Care. 2010;21:173-181.

82.

re

January-September 2017 National Health Interview Survey. 2018. Sallis RE, Baggish AL, Franklin BA, Whitehead JR. The Call for a Physical Activity

Fitzgerald L, Ozemek C, Jarrett H, Kaminsky LA. Accelerometer Validation of

na

83.

lP

Vital Sign in Clinical Practice. Am J Med. 2016;129:903-905.

Questionnaires Used in Clinical Settings to Assess MVPA. Med Sci Sports Exerc.

Oliveira VHF, Perazzo JD, Josephson RA, Deminice R, Webel AR. Association Between

Jo

84.

ur

2015;47:1538-1542.

the 6-Minute Walk Test Distance and Peak Cardiorespiratory Fitness Among People Living with HIV Varies by Fitness Level. J Assoc Nurses AIDS Care. 2018;29:775-781. 85.

Boxer R, Kleppinger A, Ahmad A, Annis K, Hager D, Kenny A. The 6-minute walk is associated with frailty and predicts mortality in older adults with heart failure. Congest Heart Fail. 2010;16:208-213.

86.

Ozemek C, Phillips SA, Popovic D, et al. Nonpharmacologic management of hypertension: a multidisciplinary approach. Curr Opin Cardiol. 2017;32:381-388.

Journal Pre-proof 87.

Rich MW, Beckham V, Wittenberg C, Leven CL, Freedland KE, Carney RM. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med. 1995;333:1190-1195.

88.

Bonato M, Turrini F, V DEZ, et al. A Mobile Application for Exercise Intervention in People Living with HIV. Med Sci Sports Exerc. 2019.

89.

Fitch KV. Contemporary Lifestyle Modification Interventions to Improve Metabolic

ro

Panza E, Wing EJ, Wing R. Behavioral Weight Loss: A Promising Treatment for Obesity

ur

na

lP

re

-p

in Adults with HIV. AIDS Behav. 2019:10.1007/s10461-10019-02645-y.

Jo

90.

of

Comorbidities in HIV. Current HIV/AIDS Reports. 2019;16:482-491.