Patients living with HIV have quantitatively inadequate food consumption

ABSTRACT Objective: The objective of the current study was to estimate energy expenditure and compare it with the usual food consumption of PLWH, and to determine whether duration of high-potency antiretroviral therapy (HAART) influenced nutritional intake and adequacy. Materials and methods: Anthropometric measurements and bioelectrical impedance analysis (BIA) provided data for estimating resting energy expenditure (REE) using Melchior's equations. Dietary Reference Intakes (DRIs) and 24-Hour Recall were used to verify if reported food intake aligned with energy, macro and micronutrient recommendations. Results: Sixty one patients with a mean age of 52 ± 9.4 years and who had a high frequency of diabetes mellitus (24.5%), hypertension (54%), and dyslipidemia (90.1%) were evaluated. Estimated REE of female and male patients with less than 10 years of HAART was 1791 (1717.5; 1887.2) and 1941 (1808; 2335.6), and their estimated energy intake was 900.5 (847;1221.9) and 2095.4 (1297.5; 2496.4), respectively. The estimated REE for female and male patients with more than 10 years of HAART was 1796.20 (1598.9;1820.7) and 2105 (1913.4; 2308), and their estimated energy intake was 1566 (1353.1; 1764.3) and 1999.7 (1706.5; 2508.1), respectively. Being on HAART for more than 10 years was associated with increased energy intake (533 (95% CI 3; 1063) kcals), but not with meeting energy requirements. Conclusion: Patients had an atherogenic metabolic profile, inadequate dietary pattern, and a similar REE, regardless of HAART duration, contributing even more to the increased risk of cardiovascular diseases.


INTRODUCTION
T he interaction of high potency antiretroviral therapy (HAART) with the inflammation and infection generated by human immunodeficiency virus (HIV) itself is associated with serious unwanted effects, such as metabolic changes and abnormal redistribution of body fat. This set of alterations is called HIVassociated lipodystrophy syndrome (1). Abnormal redistribution of body fat (lipodystrophy) is the main feature of this syndrome, being characterized by loss of subcutaneous fat mainly in the face, gluteal region and limbs (lipoatrophy), and accumulation of fat in the cervical back, breasts and visceral (lipohypertrophy). This modulation of fat can be accompanied by insulin resistance and dyslipidemia, which are features of the metabolic syndrome, and involves a set of cardiovascular disease risk factors, including hypertension, low levels of high-density lipoprotein cholesterol levels, hypertriglyceridemia, and central obesity (2).
Given that HAART is associated with several adverse metabolic effects, questions have arisen regarding the energy expenditure of people living with HIV/AIDS (PLWHA) with HAART-associated lipodystrophy (HAL) (3). A study suggested that resting energy expenditure (REE), i.e., the rate at which the body consumes energy while inactive, was considerably higher in HIV-infected patients with HAARTassociated lipodystrophy than in infected patients who did not develop lipodystrophy. An increased food and fat intake has also been linked to patients with HAL (4).
When estimating energy expenditure in clinical practice, it is more feasible to use predictive equations developed through validation studies. These equations utilize variables that are close correlated to REE, and are evaluated by being compared to a more accurate method. Melchior's equations, which were developed specifically for individuals living with HIV, are the best option for the assessment of energy expenditure in these patients (5).
Thus, the objective of the present study was to calculate the REE and total energy expenditure (TEE) using these predictive equations that are most suitable for this population. Habitual food consumption was also assessed, and used to verify whether energy and macronutrient recommendations were met or exceeded, which could exacerbate atherogenic profile and cardiovascular risk in patients with lipodystrophy syndrome. We also aimed to identify whether the duration of HAART treatment influenced energy intake.

24-hour dietary recall
The usual diet was characterized by the application of three 24-hour dietary recalls by trained interviewers. For the calculation of nutrients, Microsoft Excel software was used, through planned spreadsheets with data from the Brazilian Table of Food Composition -TACO (7).
Usual dietary intake was estimated with The Multiple Source Method (MSM), a program which calculates the usual dietary intake from 24-hour recalls using statistical methods, aiming to reach a more accurate estimate of individual values (8). Averages of these results were compared to the estimated average requirement (EAR), a reference value that corresponds to the median of the distribution of the requirement of a given nutrient in a group of healthy individuals with the same sex and stage of life, sufficient to meet the nutrient requirements of 50% of the population, present in the DRIs (dietary reference intakes) (9). Optimal intake of cholesterol, trans fatty acids, and saturated fatty acids were considered to be as low as possible while consuming a nutritionally adequate diet (10).

Anthropometric measurements and calculation of indices
Anthropometric measurements were performed at the same meeting. Body weight, in kilograms, was measured using a platform-type Filizola electronic scale, with a maximum capacity of 300 kg and accuracy of 0.1 kg. Height was measured with a stadiometer with an accuracy of 0.1 cm. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. Circumference measurements were performed using a Sanny metallic tape measure, with a precision of 0.1 cm and a maximum length of 2 m. The assessment of abdominal circumference (AC) was performed at the midpoint between the last rib and the iliac crest in a horizontal plane. Waist circumference (WC) was measured with the individual standing, using an inextensible measuring tape with graduations up to 150 cm and a minimum of 0.1 cm; the measurement was taken at the midpoint between the last rib and the iliac crest. The hip circumference (HC) was measured in the region with the greatest circumference between the abdomen and the thigh (11). The waist-hip ratio (WHR) was calculated by dividing the WC (cm) by the HC (cm) and the waist-thigh ratio (WTR) by dividing the WC (cm) by the thigh circumference (TC) (cm). The World Health Organization (WHO) reference values were used to classify risk of metabolic alterations (12).

Biochemical analyses
Serum lipid enzyme levels (total cholesterol = TC, triglycerides = TG and high-density lipoprotein = HDL)

Bioelectrical impedance analysis (BIA)
After removing excess clothes and jewellery, the individual assumed a supine position. The skin of the right hand and foot was sanitized with 70% alcohol and, after drying, the procedures began. The distal electrodes (current electrodes) were fixed on the anterior surface of the foot, on the final distal part of the second metatarsal and in the posterior area of the hand, on the final distal part of the third metacarpal. The proximal electrodes (reading electrodes) were placed on the prominence of the radius and ulna on the posterior surface of the wrist, and the other electrode between the malleolus of the tibia and fibula on the anterior surface, at the junction between the foot and leg. Subsequently, using the RJL SYSTEM ® device, a current of 50kHz was applied and the values of R and Xc in Ohm were determined to calculate fat mass and fat-free mass using the Kotler equation (13).

Predictive equations for calculating REE
The best equations for estimating REE are populationspecific, such as Melchior's, which was based on a sample of 129 people living with HIV without the presence of secondary infections, which matches the population of the present study (5). The selected Melchior equation is as follows: REE (kj/day) = 1379 + 123 x lean mass (kg) (14). The energy expenditure obtained was multiplied by the activity factor of 1.2, recommended for sedentary individuals/practitioners of light physical activity, which closely matches the level of physical activity of participants in our sample.

Statistical analysis
Data are presented as mean and standard deviation for demographic, anthropometric and body composition variables, and median alongside interquartile range (p25 -p75) for nutritional variables. Participants were separated according to the duration of HAART into < 10 years of HAART or ≥ 10 years of HAART. Baseline demographic variables between these groups were compared using Student's t test or the nonparametric Wilcoxon test for continuous variables, and the chisquare test for categorical variables.
To assess whether the duration of HAART treatment associated with current energy intake, linear regression models were used, with energy intake considered as a dependent variable, and duration of HAART (< 10 years or ≥ 10 years) as the independent variable. Additionally, to assess whether HAART treatment associated with the proportion of patients that met their energy requirements, logistic regression models were also used, this time with the classification of whether the patient met their energy requirements ("Yes" or "No") considered as the dependent variable, and duration of HAART (< 10 years or ≥ 10 years) as the independent variable. All models were adjusted for sex, age and body weight. A significant result was assumed when p < 0.05. All analyses were done using R and Rstudio software (R version 4.2.1, R Core Team, Vienna, Austria).

RESULTS
The final study sample consisted of 61 patients, with a mean age of 52 (±9.4) years, mean time of infection of 15 (±7.1) and mean time of treatment with HAART of 14 (±7). The mean age of patients with less than 10 years of HAART use was 52.5 ± 10.3, and they had a percentage of 13% of diabetes mellitus, 43% of hypertension and 82% of dyslipidemia. Regarding medication use, 17% used antidiabetic drugs, 47% antihypertensive drugs and 39% lipid-lowering drugs. In contrast, patients with longer use of HAART (more than 10 years), had a mean age of 52.5 ± 7.18, and higher presence of diabetes mellitus (31.5%), hypertension (60%) and dyslipidemia (94%). Antidiabetic drugs were used by 24.5% of this group, antihypertensive drugs by 55.7% and lipid-lowering drugs by 36% (Table 1).
All measurements for female participants were above reference values, indicating the presence of obesity and substantially higher cardiovascular risk. BMI in the female group that had been using HAART for more than 10 years was similar to the group that had been on treatment for less time, but the smaller hip and thigh circumferences may point to the development of lipodystrophy. Male patients also presented measures that exceeded the reference values. However, in the  group that used HAART for more than 10 years, the cardiovascular risk was substantially higher, as indicated by the values of waist circumference and waist-hip ratio (higher than the other male group) ( Table 2) (12). BIA indicated that lean mass and fat mass values were similar in both groups (Table 3).  Regarding food consumption, 35 individuals presented with an energy intake (kcal) below their recommendation, 15 (68%) being on HAART for less than 10 years, and 20 (51%) being on HAART for more than 10 years (Figure 1, panels A and B). Linear regression models showed that being on HAART for 10

Energy balance in HIV infection
Arch Endocrinol Metab, 2023, v.67(5), 1-10, e000623. or more years was significantly associated with higher energy intake then being on HAART for less than 10 years (Coefficient: 533 (95% CI 3; 1063) kcals, p-value = 0.04). However, being on HAART for longer duration was not associated with increased or decreased odds of having adequate energy intake (Coefficient: 2.54 (95% CI 0.79; 9.06) odds ratio, p-value = 0.129) (Figure 1, panels C and D). Average total energy intake was below the DRIs recommendations in both groups, while the percentages of lipids, proteins and carbohydrates were within the recommended range. Both groups presented, on average, inadequate ingestion of fiber and micronutrients such as potassium, iron, calcium and vitamin C, with the exception of sodium (above recommended ingestion) and zinc (adequate) ( Table 4).
When separating individuals according to sex, in males, estimated energy expenditure was higher in patients who had been using HAART for more than 10 years compared to men who had been on treatment for less time. In women, there was a slight increase in estimated energy expenditure in the group with longer use of HAART (Table 5).

DISCUSSION
A quantitatively inadequate dietary profile, high prevalence of metabolic alterations, and redistribution of body fat was observed in this group of PLWH using HAART. Statistical models showed that individuals on HAART for 10 years or longer consumed more kcals than their counterparts, even after adjusting for important confounding variables such as sex, age and body weight. HAART duration, however, was not associated with odds of having an adequate energy intake relative to individual needs, suggesting that although HAART may impact energy intake, this impact may be relatively small.
Although the food consumption evaluation revealed that some nutrients had similar intakes in both groups, some were different, such as energy, carbohydrates,

Energy balance in HIV infection
Arch Endocrinol Metab, 2023, v.67(5), 1-10, e000623.  lipids, fiber, calcium, sodium, potassium and vitamin C, indicating that patients with more than 10 years on HAART have a higher food intake. When considering the average of the entire group, insufficient intake of energy, some micronutrients (potassium, iron, calcium and vitamin C) and fiber, in addition to a high consumption of sodium, was observed in both groups, when compared to DRIs (9). A study with a similar sample to ours carried out by Duran and cols. (2008), showed an inadequate dietary pattern and a high prevalence of risk factors related to the development or progression of cardiovascular diseases in these patients, which, alongside our results, reinforces the conclusion that PLWH using HAART are likely to present with unhealthy diets (15). No considerable differences were observed in the resting energy expenditure of our sample between men and women of the two groups who used HAART for more or less than 10 years. In contrast, in the study by Sutinen and Yki-Järvinen (2007), differences were observed in a group that used HAART without lipodystrophy (HAART-LD) when it was compared to another that also used HAART, but that presented with lipodystrophy (HAART+LD). The HAART+LD group
presented a higher energy expenditure and a higher food intake, which was expected in view of the higher energy expenditure (4). This may help explain our findings. Since most patients in our sample presented lipodystrophy, their energy expenditure was similar across both groups, regardless of the time they had been on HAART. Additionally, logistic regression showed that duration of HAART did not influence the odds of reaching energy recommendations, despite HAART affecting energy intake on average. This suggests that although longer durations of HAART use may be associated with increased energy intake, this increase is not sufficient to lead to adequate energy intake.
It is undeniable that HAART has brought several advantages to patients who use it, but also that its use may be linked to metabolic changes and with the consequent development of diabetes mellitus, hypertension and dyslipidemia. This was observed in our study, where we found a higher prevalence of patients with longer time on HAART who had these comorbidities compared to those who used the therapy for less time. The same happened in the study by Tasca and cols. (2021), which evaluated 94 patients in São Paulo, and reported that patients who used antiretroviral drugs, especially those who used them for a longer time, developed metabolic and cardiac alterations (16). Such alterations can be explained by the fact that adipose tissue is one of the main factors for the development of metabolic alterations and chronic diseases, and its redistribution is the focus of lipodystrophic syndrome (17). The association between lipodystrophy and HAART exists because protease inhibitors impair adipocyte differentiation through mechanisms that include the inhibition of proteins that are part of lipid metabolism and insulin dysregulation, resulting in adipose hypertrophy (especially in the viscera), decreased high-density lipoprotein (HDL), increased triglycerides, insulin resistance, type 2 diabetes mellitus, and hypertension (18).
These factors can lead to the presence of metabolic syndrome. This syndrome was found in about half of the sample of a study by Vargas-Pacherrez and cols. (19), which estimated the presence of metabolic syndrome and associated factors in a group of people living with HIV on antiretroviral therapy. This parameter was also evaluated within our study, but no influence of time of HAART use was observed. We found high values of waist, hip and thigh circumference in both groups, regardless of the duration of HAART. However, when separated according to sex, men with longer duration of HAART exhibited a considerably higher cardiovascular risk, according to the values of waist circumference and waist-hip-ratio. Studies suggest that metabolic syndrome in HIV is also influenced by the use of antiretroviral drugs, which consequently means that these patients will have a greater accumulation of visceral fat (20). These alterations are characteristic of an atherogenic metabolic profile, which may further increase the risk of developing cardiovascular disease (17).
The main strength of our study was that it evaluated the food intake of patients and compared it with their energy expenditure, since it is known that, regardless of HIV infection, an inadequate dietary pattern is associated with risk factors for the development of cardiovascular diseases (21). In addition, although it does not have the power to completely remove all errors, the MSM program is a useful and free tool to minimize intrapersonal variance, and generate data that are most representative possible from the usual diet.
Our study also has some limitations. We acknowledge that there are other factors that may influence the assessment of food intake that were not addressed in this study, including an underreporting of energy intake in repeated 24-hour recalls, and the presence of metabolic syndrome as an inclusion criterion, since the onset of the syndrome is usually associated with an unhealthy dietary pattern. Future studies should continue investigating the influence of varying durations of HAART use on metabolic and anthropometric parameters, in addition to food intake and energy expenditure, in order to verify these findings.
In conclusion, patients within the current study showed an atherogenic metabolic profile, an inadequate dietary pattern, and a similar REE, regardless of duration of HAART, which may exacerbate cardiovascular disease risk in PLWH. Thus, treatment for human immunodeficiency syndrome should not be carried out in isolation with the use of drugs such as antiretroviral drugs, but in conjunction with the adoption of a healthy, balanced and nutritionally adequate diet, in addition to the practice of physical activities.
Author contributions: Bárbara Ferreira Vercesi -analysis of the results obtained, writing of the scientific article. Izabela Spereta Moscardini -data collection and review of article writing. Gabriel Perri Esteves -statistical analysis and review of the article's writing. Rebeca Antunes Beraldo -research coordination, data collection, statistical analysis and review of the article's writing.

SUPPLEMENTARY MATERIAL 2
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