nutrients

Article

Nutritional Intervention Reduces Dyslipidemia, Fasting

Glucose and Blood Pressure in People Living with HIV/AIDS
in Antiretroviral Therapy: A Randomized Clinical Trial
Comparing Two Nutritional Interventions
Erika Aparecida Silveira 1,2,* , Marianne Oliveira Falco 2, Annelisa Silva e Alves de Carvalho Santos 2 ,
Matias Noll 3 and Cesar de Oliveira 1,*
1
Department of Epidemiology & Public Health, Institute of Epidemiology & Health Care,
University College London, London WC1E 6BT, UK
2
Postgraduate Program in Health Sciences, Faculty of Medicine, Federal University of Goiás,
Goiânia 74605-050, Brazil; marianne.falco@gmail.com (M.O.F.); annelisa.nut@gmail.com (A.S.e.A.d.C.S.)
3
Department of Public Health, Instituto Federal Goiano, Ceres 76300-000, Brazil; matiasnoll@yahoo.com.br
* Correspondence: erikasil@terra.com.br (E.A.S.); c.oliveira@ucl.ac.uk (C.d.O.)

Received: 10 July 2020; Accepted: 23 September 2020; Published: 28 September 2020

Abstract: Antiretroviral therapy (ART) increases the risk of cardiometabolic diseases in people living with
HIV/AIDS (PLWHA). However, there is a lack of evidence regarding the effectiveness of a nutritional
intervention on several cardiometabolic parameters in this population. Therefore, this study aimed to
evaluate the effectiveness of two nutritional interventions on several cardiometabolic parameters in
PLWHA treated with ART. A parallel randomized clinical trial was performed with PLWHA treated with ART.
The participants (n = 88) were divided into two intervention groups: (1) nutritional counseling (n = 44) and
(2) individualized dietary prescription (n = 44). The follow-up period was 30 weeks. A reduction in low-
density lipoprotein (LDL) was the primary outcome. Secondary outcome variables were reductions in total
cholesterol (TC), triglycerides (TG), fasting plasma glucose (FPG), systolic and diastolic blood pressures (SBP
and DBP, respectively), waist circumference (WC), body mass index (BMI), and increases in high-density
lipoproteins (HDL). A multiple linear regression was used to analyze the effectiveness of the interventions,
adjusted for sociodemographic, lifestyle, and clinical characteristics. Sixty-two PLWHA completed the trial
(nutritional counseling, n = 32; individualized dietary prescription, n = 30). At follow-up, we observed in the
nutritional counseling group significant reductions in SBP (p = 0.036) and DBP (p = 0.001). Significant
reductions in FPG (p = 0.008) and DBP (p = 0.023) were found in the individualized dietary prescription
group. In the fully adjusted models, significant reductions in LDL, SBP, DBP, and BMI were found in the
individualized dietary prescription group. In conclusion, the two investigated nutritional interventions were
effective in reducing some cardiometabolic risk factors in PLWHA. However, after adjustments for
covariates, the individualized dietary prescription showed significant reductions in the primary outcome
and, also, in more cardiometabolic risk factors than the nutritional counseling.

Keywords: HIV; AIDS; antiretroviral therapy; dyslipidemia; cardiometabolic risk factors; dietary
intervention; nutritional counseling; individualized dietary prescription
Nutrients 2020, 12, 2970 2 of 18
Nutrients 2020, 12, 2970; doi:10.3390/nu12102970 www.mdpi.com/journal/nutrients

1. Introduction
Despitetheimmensebenefitsthatantiretroviraltherapy(ART)usehasbroughttopeoplelivingwith HIV/AIDS
(PLWHA), there are some associated increased risks of dyslipidemia, hyperglycemia/diabetes,
gastrointestinal symptoms, obesity, and hypertension, which contribute to a higher cardiometabolic risk in
this population [1–7]. Other risk factors also corroborate for cardiometabolic diseases in PLWHA, such as
smoking, excessive alcohol consumption, and physical inactivity [1,8–12].
Clinical treatment guidelines for PLWHA include prevention and treatment of cardiometabolic risk
factors. However, most of the clinical recommendations are based on drug treatments [13]. Therefore, it is
important to explore non-pharmacological treatments. Reducing cardiometabolic risk factors is essential in
the treatment of PLWHA in ART, and nutritional interventions have an important role in the management of
metabolic abnormalities [14].
There is little evidence on the effectiveness of nutritional treatment on metabolic abnormalities in
PLWHA, specially dyslipidemia, fasting plasma glucose (FPG), blood pressure, body mass index (BMI), and
waist circumference (WC) in PLWHA treated with ART [10,15–20]. In a meta-analysis that evaluated the
effects of dietary interventions on HIV-associated dyslipidemia, most studies evaluated specific nutrient
supplementation and only few studies evaluated dietary interventions, often combined with exercise
programs [15]. With regard to dietary interventions, most studies followed recommendations from general
guidelines [16,21,22], but none of the previous studies had analyzed and compared the effectiveness of
different nutritional treatment approaches [15,23].
The type of nutritional approach with a difference in the number of dietitian consultations and
prescription could influence the dietetic treatment and, consequently, reduce the cardiometabolic
outcomes. According to the above concern, our study is based on the following research question: Could an
individualized dietary prescription with one consultation per month be a more appropriate and effective
approach in reducing cardiometabolic risk factors in PLWHA than nutritional counseling with fewer dietitian
consultations? Therefore, it is important to analyze whether different nutritional approaches can lead to
different cardiometabolic outcomes [24–26].
In this context, this study aims to investigate the effectiveness of two nutritional treatment approaches
on cardiometabolic risk factors reduction in PLWHA treated with ART. The included cardiometabolic risk
factors were dyslipidemia, FPG, blood pressure, BMI, and WC. We also investigated
whether the effectiveness of these two interventions (nutritional counseling and individualized dietary
prescription) could be modified by sociodemographic, lifestyle, and clinical characteristics.

2. Methods

2.1. Study Design

This study was an open controlled randomized clinical trial (RCT) with parallel intervention, nested
within a major clinical cohort entitled Predictors of cardiovascular disease in PLWHA (PRECOR) [2]. The
PRECOR study aimed to assess cardiovascular risk and metabolic abnormalities in PLWHA being monitored in
a referral hospital for the care of infectious and parasitic diseases. The RCT was named PRECOR-NUT [6,7,27]
and registered at ClinicalTrials.gov (NCT02180035). Data collection was performed in the outpatient clinic of
the Infectious and Parasitic Diseases Service of the Clinical Hospital of the Federal University de Goiás,
Goiânia, Brazil. This is a reference outpatient clinic in the treatment of HIV/AIDS in the State of Goiás.
Eligible individuals were HIV-infected adults aged 19 years or older treated with ART for at least 30 days
attending the outpatient clinic at the time of recruitment. Exclusion criteria were pregnancy or lactation and
diagnosis of any opportunistic disease in the last 2 months prior to enrollment in the major study.
Before starting baseline procedures, training and standardization of the entire data collection were
conducted. The research team consisted of a cardiologist, physical educator, nutritionist, and
anthropometrist. The training was very detailed, especially for nutritionists involved in the interventional
procedures and for those responsible for the anthropometric measurements [28], to ensure high quality and
uniformity of all procedures.
Nutrients 2020, 12, 2970 3 of 18
2.2. Baseline
Before randomization, at baseline, the nutritionist applied a standardized structured questionnaire
covering clinical and lifestyle variables such as smoking status, alcohol consumption, and physical activity.
After the first consultation with the nutritionist, the anthropometrist performed anthropometric
measurements including of body weight, height, and waist circumference.

2.3. Enrollment and Randomization

The PRECOR cohort study consisted of 337 PLWHA. During routine care with the infectious disease
physician at the Infectious and Parasitic Diseases Service, eligible individuals were referred to a consultation
with the cardiologist who conducted a structured questionnaire covering sociodemographic and clinical
questions and requested biochemical tests, i.e., lipid profile and fasting plasma glucose.
The eligible PRECOR participants were referred to the nutritionist, who invited them to participate in
this study. Upon acceptance, the individuals signed to give informed consent and 88 participants were
randomly allocated to one of the two intervention groups in a 1:1 ratio according to a random sequence
generated by a randomization website. This study had two arms: a nutritional counseling group and a diet
group. The interventions started with 88 PLWHA, 44 in each arm. The sample size estimate was performed
based on the central limit theorem. According to this theorem, a sample with a size equal to or greater than
30 tends to present normality in the distribution of means and is also enough to find significant differences
[29].
Out of the 337 PLWHA participating in the PRECOR cohort study, 176 patients were randomized to
participate in the present study since 54 patients did not attended the first nutrition consultation,
101 were ART naïve patients, and 6 declined to participate. Out of the 176 randomized referred patients, 88
were allocated to another study (Figure 1).

2.4. Blinding
After randomization, patients’ appointments were scheduled on different days of the week to avoid
contact between groups and prevent information exchange regarding the received intervention.

2.5. Intervention Protocols

There were two intervention groups: (1) nutritional counseling and (2) individualized dietary
prescription. The individualized dietary prescription takes into account the energy and nutritional needs of
each individual in addition to their biopsychosocial context. In both groups, nutritional care was provided by
a trained nutritionist. The nutritional counseling group received nutritional guidance on promoting healthy
eating using the “10 steps to healthy eating” folder, from the Brazilian Ministry of Health [30], that is part of
the first edition of the Nutritional Guide for the Brazilian Population, which was the only version available at
the time of the study.
Nutrients 2020, 12, 2970 4 of 18

Figure 1. Flowchart of entry in clinical trial and follow-up of the participants in groups-nutritional counseling group
and diet group. Completers’ analysis.

The 10 healthy eating steps were as follows: (1) Make at least three meals (breakfast, lunch, and dinner)
and two healthy snacks per day. Do not skip meals. (2) Include six portions of the cereal group (rice, corn,
wheat, bread and pasta), tubers such as potatoes and roots such as cassava in meals. Give preference to
whole grains and foods in their most natural form. (3) Eat at least three servings of vegetables daily as part of
meals and three or more servings of fruit in desserts and snacks. (4) Eat beans with rice every day or at least
five times a week. This Brazilian dish is a complete combination of proteins and good for health. (5) Consume
three servings of milk and dairy products daily and a portion of meats, poultry, fish, or eggs. Removing the
apparent fat from meat and poultry skin prior to preparation makes these foods healthier! (6) Consume a
maximum of one portion per day of vegetable oils, olive oil, butter, or margarine. Watch for food labels and
choose those with the lowest amounts of trans-fats. (7) Avoid soft drinks and processed juices, cakes, sweet
and stuffed biscuits, sweet desserts, and other treats as a rule for feeding. (8) Decrease the amount of salt in
the food and remove the saltshaker from the table. Avoid consuming high-sodium (processed) foods such as
hamburger, sausage, ham, snacks, canned vegetables, soups, and ready-to-eat sauces and seasonings. (9)
Drink at least two liters (six to eight glasses) of water a day. Give preference to water consumption during
meal breaks. (10) Make your life healthier. Practice at least 30 min of physical activity every day and avoid
alcoholic beverages and smoking. Keep your weight within healthy limits.
The individualized dietary prescription group received a healthy eating plan which contained an
individualized menu with mealtimes and a list of equivalent foods for each food group (bread/biscuit,
milk/cheese, fruits, beans, vegetables, meat, oil/butter, sugar/candies) quantified in standard serving sizes
using common kitchen measurements [31]. The healthy eating plan prescription took into consideration the
socioeconomic status, lifestyle, and eating habits of each study participant. The nutritionists calculated
individual energy and protein requirements [32] as well as the resting energy expenditure [33]. Adjusted
Nutrients 2020, 12, 2970 5 of 18
weight was used for obese and underweight participants [34]. The daily macronutrient distribution range
according to the total energy value was 55% to 60% carbohydrate, 25% to 30% fat, 15% protein, along with
20 to 30 g of dietary fiber [13,35]. The diet group received instructions to not consume foods containing
trans-fat [13,31,35]. In addition, this group was instructed to prepare meals with less fat and sugar,
prioritizing baking, grilling, and steaming while avoiding frying. Patients in both groups received nutritional
guidelines as informative standard forms in case of hypercholesterolemia, hypertriglyceridemia,
hypertension, and diabetes, independently of the intervention group to which they were allocated [31].

2.6. Follow-Up
The nutritional treatment and follow-up visits were specific to each group. Both groups were followed
for approximately 30 weeks. After randomization, return visits were scheduled at week 14–15 for the
nutritional counseling group and at every four or five weeks for the diet group. This difference in the number
of consultations is part of the intervention style which we are testing.
During each follow-up visit, food intake, body weight, and waist circumference were assessed. The
compliance to dietary intervention was carried out by assiduity in return visits and by the dietitian’s
perception during consultations. The compliance to the dietary intervention was evaluated by one registered
dietitian who received training to assess participants’ motivation and standardize the treatment protocols
and approaches. The decision to have only one dietitian was a strategy to provide and ensure standardized
treatment in both groups. Therefore, the same nutritionist provided patient care throughout the study,
strengthening the professional–patient relationship.

2.7. Study Variables

The study variables analyzed were sociodemographic (sex, age, skin color, marital status, income, and
educational level); lifestyle (smoking status, alcohol consumption, and physical inactivity); clinical (family
history of cardiovascular disease, viral load, time of ART use, class of antiretroviral drug, and blood pressure);
anthropometric (body weight, height, WC, and BMI) and biochemical (lipid profile and fasting plasma
glucose).

2.7.1. Sociodemographic Variables

Income was collected according to patients’ monthly income and grouped into quartiles in Brazilian real
(BRL-R$): 1st quartile, minimum income up to R$509.00; 2nd quartile, income from R$510.00 to R$699.00;
3rd quartile income from R$700.00 to R$1199.00, and 4th quartile, income equal to or greater than
R$1200.00. The average exchange rate during the study period was 1 USD = 3.57 BRL. Schooling years were
grouped into four categories: up to 4 years; 5 to 8 years; 9 to 11 years; and 12 or more years of study.

2.7.2. Lifestyle Variables

Smokers were considered those who smoked or stopped smoking less than six months prior to the
study, while non-smokers and ex-smokers were those who stopped smoking for more than 6 months prior to
the study [36].
Alcohol consumption was investigated according to the type of beverage, frequency, and amount
(doses, bottles, or glasses) consumed in the week prior to the first study interview [37]. The amount of
alcoholic beverages consumed was converted to grams of ethanol per day.
Physical activity was assessed using the short version of the International Physical Activity
Questionnaire (IPAQ) [38,39]. Those with no or low levels of physical activity were classified as sedentary,
i.e., a score less than 600 MET-min/week [38,39].

2.7.3. Clinical Variables

Viral load values (copies/mL) were classified as <50 (undetectable viral load) and ≥50 [ 40,41].
Antiretrovirals drugs were categorized into nucleoside-analogue reverse transcriptase inhibitors (NRTI), non-
nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI).
The Welch Allyn/Tycos aneroid sphygmomanometer was used to measure arterial blood pressure. The
participant was asked to sit with their legs uncrossed, back supported, and their arm positioned so that the
upper part of the cuff was at the height of the midpoint of the sternum. Three successive measurements
were taken with a one-minute interval between measurements. The first measurement
Nutrients 2020, 12, 2970 6 of 18
was performed after five minutes of rest [42–44].

2.7.4. Anthropometric Variables

The anthropometric variables (body weight, height, and WC) were measured according to a
standardized protocol [45]. The Tanita BC558-Ironman digital scale with a capacity of 150 kg and an accuracy
of 100 g was used to measure body weight. For the height measurement, we used a tape affixed to a wall
with an accuracy of 0.1 cm. The BMI value was calculated by dividing body weight in kilograms by the square
of height in meters.

2.7.5. Biochemical Variables

For the biochemical tests, study participants were asked to fast for 12 h and avoid consumption of
alcohol for three days before blood collection. The total lipid profile values were obtained by an automated
enzymatic method following established techniques [46,47]. LDL was calculated using the Friedewald et al.
equation [48] if triglycerides < 400 mg/dL. LDL was defined as the primary outcome. The fasting plasma
glucose was obtained through biochemical analysis in peripheral blood.

2.8. Ethical Considerations

This RCT was conducted according to the ethical standards established in the Declaration of Helsinki.
The Ethics Committee on Medical, Human and Animal Research of the Federal University of Goiás Clinical
Hospital approved the study protocol (no. 163/2009).

2.9. Statistical Analysis

The Shapiro–Wilk test was used to assess the normality of the continuous data distribution. Pearson’s
Chi-squared and Fisher’s exact tests were used in the bivariate analyses. The paired and unpaired Student’s t-
test, Wilcoxon test, and Mann–Whitney test (nonparametric data) were employed for the continuous
variables. McNemar’s test was used to compare paired categorical variables at baseline and at the end of
follow-up in each intervention group.
The primary outcome was LDL reduction. Secondary outcomes were reductions in TC, TG, FPG, SBP,
DBP, WC, and BMI. We also analyzed the increase in HDL as an outcome. The effectiveness of each treatment
on the outcome variables was calculated by the difference between baseline and final follow-up values for
each intervention group [49].
We performed linear regression between the outcomes and the independent variables. Those
associations that showed a p-value smaller than or equal to 0.20 at this stage of analysis were included in the
multiple linear regression analysis. Lastly, only those variables with a p-value smaller than or equal to 0.05
were kept in the final multiple linear regression models.
The database was structured in EpiData version 3.0 with double entry. All analyzes were performed
using the Stata 12® statistical program (Stata Corp, College Station, TX, USA).
3. Results
Out of 176 individuals referred to this study from the 337 PLWHA participating in the PRECOR cohort
study, 88 were allocated to another clinical trial study. Therefore, the present study comprised 88
participants, with 44 allocated to the nutritional counseling group and 44 to the diet group. Losses of follow-
up and exclusions with reasons are displayed in Figure 1. Sixty-two patients successfully completed the study
and were analyzed at the end of follow-up, after approximately 30 weeks, with 32 participants being in the
nutritional counseling group and 30 participants in the individualized dietary prescription group.
The main sociodemographic characteristics of the included PLWHA were 67.74% men, 48.39% had
brown/black skin, 54.84% had a monthly income higher than R$700.00, and 59.68% had nine or more years
of education (Table 1). Regarding lifestyle, 61.29% did not smoke, 51.61% consumed alcohol, and 58.06%
were physically inactive. The ART use time was over three years in 33.33% of the participants, and 70.40%
used it for over six months. After randomization, both intervention groups were similar except in relation to
their FPG (Table 1). NRTIs are not presented in the tables because all PLWHA used these drugs.

Table 1. Sociodemographic, clinical, and cardiometabolic data at baseline for people living with HIV/AIDS (PLWHA)
according to their allocated groups.
Variables n (%) Nutritional Counseling Group n (%) Diet p-
Group
Nutrients 2020, 12, 2970 7 of 18
Total = 62 n (%) Value

Age groups 0.821 †

50 or above 9 (14.52) 4 (44.44)

Marital status 0.355 †

Income quartiles 0.602 †

1st (poorest) 13 (20.97) 5 (38.46) 8 (61.54)

2nd 15 (24.19) 9 (60.00) 6 (40.00)

3rd 13 (20.97) 8 (61.54) 5 (38.46)

4th (richest) 21 (33.87) 10 (47.62) 11 (52.38)

Education, schooling 0.526 †

years
≤4 years 8 (12.90) 4 (50.00) 4 (50.00) 5–8 years 17 (27.42) 8 (47.06) 9 (52.94)
9–11 years 20 (32.26) 13 (65.00) 7 (35.00)
>11 years 17 (27.42) 7 (41.18) 10 (58.82)

Table 1. Cont.
n Nutritional Counseling Group n (%) Diet
(%) Grou p-
Variables
Total = pn Value
62 (%)
Sedentary behavior 0.06
5*
Yes 36 15 (41.67) 21 (58.33)
(58.06
)
No 26 17 (65.38) 9 (34.62)
(41.94
)
Family History of 0.23
Cardiovascular Disease 0†
Nutrients 2020, 12, 2970 8 of 18
Yes 2 - 2 (100.00)
(3.23
)
No 60 32 (53.33) 28 (46.67)
(96.77
)
Viral load 0.11
0†
<50 copies/mL 47 22 (46.81) 25 (53.19)
(79.66
)
≥ 12 9 (75.00) 3 (25.00)
50 copies/mL
(20.34
)
ART usage time 0.13
5†
≤ 16 12 (75.00) 4 (25.00)
0.5 years
(29.63
)
0.5–1 year 5 4 (80.00) 1 (20.00)
(9.26
)
1–3 years 15 9 (60.00) 6 (40.00)
(27.78
)
>3 years 18 6 (33.33) 12 (66.67)
(33.33
)
NNRTI 0.20
4*
Yes 43 20 (46.51) 23 (53.49)
(71.67
)
No 17 11 (64.71) 6 (35.29)
(28.33
)
Protease Inhibitor 0.05
0†
Yes 18 13 (72.22) 5 (27.78)
(30.00
)
No 42 18 (42.86) 24 (57.14)
(70.00
)
Average ± SD Average ± SD

Waist Circumference 62 ± ± 0.17

84.65 9.39 88.02 10.03
7‡
2) 62 ± ± 0.19
23.81 3.55 25.05 3.90
7
dL 62 ± ± 0.09
178.34 47.59 197.80 43.62
9
dL) 62 ± ± 0.12
103.72 37.79 119.10 38.78
2
dL) 62 ± 0.28
44.00 12.26
7

dL) 62 ± ± 0.46
167.88 71.64 187.97 90.33
4
d 62 ± ± 0.00
83.53 7.73 89.80 7.96
L) 3
Systolic pressure (mmHg) 62 ± ± 0.58
117.53 13.17 119.40 13.77
7
Diastolic pressure (mmHg) 62 ± ± 0.50
82.13 8.43 80.57 9.78
3‡
Values are n (%) or average ± SD. * Values obtained by Pearson X 2 test. † Values obtained by Fischer Exact Test. ‡ Values
obtained by Student’s t-test for independent variables. § Values obtained by Mann–Whitney U-test for independent non-
parametric variables. PLWHA: People living with HIV/AIDS; ART: antiretroviral therapy; BMI: body mass index; HDL-C: high-
density lipoprotein; LDL-C: low-density lipoprotein; NNRTI: non-nucleoside reverse transcriptase inhibitors; SD: standard
deviation.
Nutrients 2020, 12, 2970 9 of 18
Comparing the data from baseline to the end of follow-up within each group, there was a statistically
significant reduction in DBP for both groups. The individualized dietary prescription group had a significant
reduction in FPG (p = 0.008). The nutritional counseling group had statistically significant decreases in SBP ( p
= 0.036) and DBP (p < 0.001) (Table 2).
In both groups, a reduction in LDL, TC TG, FPG, SBP, DBP, and WC, and an increase in HDL values
between baseline and the end of follow-up were observed. Clinically, the reduction in TC, LDL, TG, FPG, and
WC were more expressive in the individualized dietary prescription group. Regarding
WC, in the individualized dietary prescription group, there was a reduction of 1.74 cm, while in the
nutritional counseling group, there was a reduction of only 0.30 cm. With respect to BMI, it was reduced only
in the individualized dietary prescription group (−0.36 kg/m 2), while there was an increase in the nutritional
counseling group (0.22 kg/m2) (Table 3).
Table 2. Cardiometabolic variables: comparison of baseline data with the end of follow-up for each group of the
randomized clinical trial.
Nutritional Counseling Group Diet Group
Variables
n Baseline Follow-up p-Value * n Baseline Follow-up p-Value *
Dyslipidemia 32 31 (96.88) 21 (65.63) 0.002 † 30 29 (96.67) 22 (73.33) 0.039 †
Isolated
32 4 (12.50) 2 (6.25) 0.500 † 28 3 (10.70) 3 (10.70) 1.000 †
hypercholesterolemia a
Hypertriglyceridemia 32 18 (56.25) 11 (34.38) 0.092 † 30 20 (66.67) 12 (40.00) 0.032 †
± ±
Average SD Average SD

Total cholesterol ± ± ± ±
32 178.34 47.59 174.00 43.88 0.423 30 197.80 43.62 188.40 37.32 0.099
(mg/dL)
#
LDL (mg/dL) 32 ± ± 0.479 28 ± ± 0.143
103.72 37.79 100.84 34.35 119.57 39.41 109.54 40.81

HDL (mg/dL) 32 ± ± 0.095 30 ± ± 0.266 ‡

40.72 10.13 43.56 10.06 44.00 12.26 45.80 14.31
Triglyceride (mg/dL) 32 ± ± 0.112 30 ± ± 0.089 ‡
167.88 71.64 146.44 69.21 187.97 90.33 160.43 91.28

Fasting plasma glucose ± ± ± ±

32 83.53 7.73 81.91 8.37 0.275 30 90.14 7.88 86.38 9.72 0.008 ‡
(mg/dL)
Systolic pressure ± ± ± ±
32 117.53 13.17 113.34 10.94 0.036 30 119.40 13.77 115.03 9.39 0.066
(mmHg)
Diastolic pressure ± ± ± ±
32 82.13 8.43 76.94 7.73 0.0009 30 80.57 9.78 77.20 7.10 0.023
(mmHg)
Waist circumference (cm) ± ± ± ±
32 84.65 9.39 84.42 9.38 0.774 26 § 88.77 10.53 87.03 9.99 0.068

BMI (kg/m2) 32 ± ± 0.617 26 § ± ± 0.151

23.81 3.55 24.03 3.72 25.14 4.12 24.78 4.09
Values are n (%) or average ± SD. a PLWHA without other associated dyslipidemias. * Values obtained by Student’s t-test for
paired variables. † Values obtained by McNemar’s test for paired and categorical variables. ‡ Values obtained by Wilcoxon
test for non-parametric paired variables. § Four PLWHA did not follow up to anthropometry. BMI: body mass index; HDL:
high-density lipoprotein; LDL: low-density lipoprotein; SD: standard deviation. # The two missing individuals in the LDL group
occurred due to missing blood assays in the laboratory.

Table 3. Effectiveness of each nutritional treatment on cardiometabolic variables.

Nutritional Counseling Group * Average Diet Group *
Variables n
± SD Average ± SD
Total cholesterol (mg/dL) 62 − ± − ±
4.34 30.25 9.40 30.22
LDL (mg/dL) 60 − ± − ±
2.88 22.70 10.04 35.18
HDL (mg/dL) 62 ± ±
2.84 9.34 1.80 8.22
Triglyceride (mg/dL) 58 − ± − ±
21.44 74.16 27.53 80.43
Fasting plasma Glucose(mg/dL) 58 − ± − ±
1.63 8.27 3.76 8.35
Systolic pressure (mmHg) 62 − ± − ±
4.19 10.80 4.37 12.52
Diastolic pressure (mmHg) 62 − ± − ±
5.19 7.95 3.37 7.61
Waist circumference (cm) 58 − ± − ±
0.28 4.52 1.74 4.65
2
BMI (kg/m ) 58 ± − ±
0.22 2.41 0.36 1.22
* Values refer to the average difference of the results between the baseline and the end of follow-up. Values are average ±
standard deviation (SD). Negative values represent a decrease and positive values represent an increase. BMI, body mass
index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD: standard deviation.
Nutrients 2020, 12, 2970 10 of 18
In the nutritional counseling group, the variables included in the multiple linear regression analysis for
each outcome were as follows: income for TC; sex, income, smoking, ART time use, and NNRTI for LDL;
income, education, and smoking for HDL; sex and age for TG; age, skin color, ART time use, NNRTI, and IP for
FPG; smoking and time of ART use for SBP; skin color and income for WC (p-value < 0.20). After multiple
linear regression, HDL was reduced by 4.6 mg/dL (p = 0.013) among those patients in the 4th quartile of
income, TG increased to 12.57 mg/dL (p = 0.019) in those aged 40 years or more and WC also increased to
1.48 cm (p = 0.036) in those with brown/black skin. In this group, SBP was reduced by 0.27 mmHg in those
using ART for more than a year (p = 0.024). Despite the four significant p-values in both intervention groups,
the primary outcome LDL was significant only in the diet group. Both interventions showed reductions in
cardiometabolic risk factors for HIV patients (Table 4).
Nutrients 2020, 12, 2970
10 of 16

Table 4. Multiple linear regression of the effectiveness of each nutritional treatment on cardiometabolic outcomes.
Variables Nutritional Counseling Group Diet Group

Adjusted β * (95% Adjusted β *

A CI) Effectiveness R2 p-Value α (95% CI) Effectiveness † R2 p-Value

Total cholesterol
- - - - - - - - - -
(mg/dL)
−
27.50
LDL −
- - - - - 2.74 − − 24.76 0.158 0.036
(mg/dL) ( 53.13 to 1.87)
brown/black skin
−
12.94
HDL −
8.34 − − 4.6 0.206 0.013 - - - - -
(mg/dL) ( 22.93 to 2.93) income
4◦ quartile
60.46
Triglyceride (mg/dL) − (10.44–110.48) 12.57 0.169 0.019 - - - - -
47.89
Age > 40 years
Fasting plasma
- - - - - - - - - -
glucose (mg/dL)
8.48 −
11.75
Systolic pressure − (1.19–15.77) − − −
8.75 0.27 0.163 0.024 0.45 − − 12.2 0.202 0.013
(mmHg) >1 year of ART ( 20.78 to 2.72)
female
7.83
Diastolic pressure − −
- - - - - 17.68 (0.58–15.18) IP 9.85 0.154 0.035
(mmHg)

Waist 3.31
circumference (cm) − (0.22–6.40) 1.48 0.138 0.036 - - -
1.83
brown/black skin
1.15
BMI (kg/m2) - - - − (0.09–2.22) − 0.238 0.035
1.18 0.03
>3 years of ART
The values were obtained by a multiple lineal regression analysis. * Values were adjusted by sex, age, income, smoking, alcohol consumption, inactivity, family history of cardiovascular disease, ART usage
time, protease inhibitor, non-nucleoside reverse transcriptase inhibitors/and nucleoside reverse transcriptase inhibitors. Blank spaces mean that none of the adjusted variables modified the effectiveness
in cardiometabolic outcomes. † Effectiveness: difference among the values of each outcome variable between the baseline and the end of the follow-up. BMI, body mass index; ART, antiretroviral therapy;
HDL, high-density lipoprotein; LDL, low-density lipoprotein; PI, protease inhibitor.
Nutrients 2020, 12, 2970 12 of 18

In the individualized dietary prescription group, the following variables were included in the multiple
linear regression analysis: ART time use, family history of cardiovascular disease, and alcohol consumption
for TC; skin color, family history of cardiovascular disease for LDL; income and ART time use for HDL; skin
color, age, income, smoking, and ART time use for TG; income, education, and NNRTI for FPG; skin color,
physical inactivity, alcohol consumption, and IP for DBP; sex, skin color, and consumption of alcoholic
beverages for SBP; sex for WC; and ART time use for BMI (p-value < 0.20). There were statistically significant
reductions in the following: LDL (−24.76 mg/dL) in those with brown/black skin, SBP (−12.20 mg/dL) in
women, DBP (−9.85 mmHg) in those using IP and BMI (−0.03 kg/m 2) between those who used ART for more
than three years (Table 4).

4. Discussion
To the best of the authors’ knowledge, this is the first clinical trial with PLWHA treated with ART that
demonstrated the effectiveness of nutritional intervention on reducing several cardiometabolic risk factors in
both nutritional intervention groups, i.e., nutritional counseling and individualized dietary prescription. In the
nutritional counseling group, significant reductions were observed for systolic and diastolic blood pressure,
while in the individualized dietary prescription group, significant reductions were observed for diastolic
blood pressure and fasting plasma glucose. In the multivariate model with subgroup analysis, we found that
sociodemographic, lifestyle, and clinical parameters can influence the effectiveness of some outcomes, an
important contribution of this RCT. More effective reductions were found in the individualized dietary
prescription group compared to the nutritional counseling group. However, the nutritional counseling could
also be applied in HIV/AIDS ambulatory care settings if there were not enough dietitians to prescribe
individualized diets.
In both groups, the nutritional treatment significantly decreased DBP levels. In the nutritional
counseling group, we observed SBP decreases, while in the individualized dietary prescription group, the
reduction was relevant but of marginal significance. Only another RCT found reductions in SBP [50], however,
it included nutritional intervention and physical activity. RCTs with nutritional counseling found no
reductions in DBP and SBP [22]. In our study, the average reduction in DBP was up to 5.2 mmHg and was 4.4
mmHg for SBP. These reductions may have an important clinical role in controlling blood pressure in PLWHA,
especially considering that the average blood pressure in both groups at baseline was normotensive.
Nutritional treatment for PLWHA may have an important preventive role in hypertension, especially
considering that blood pressure increases significantly during 96 weeks of antiretroviral use [51]. Some
evidence recommends the DASH diet or the Mediterranean diet for the management of hypertension [52];
however, this type of diet is not part of the eating habits of most PLWHA, since two-thirds of PLWHA live in
the Americas and sub-Saharan Africa [53]. However, the present study provided a reduction in DBP and SBP
with nutrition advice or individualized dietary prescription, respecting regional eating habits.
Fasting plasma glucose showed a statistically significant reduction in the individualized dietary
prescription group with an average reduction of 3.8 mg/dL. The few studies that evaluated FPG in PLWHA
treated with ART observed no reduction in glycemic parameters when prescribing dietary interventions [ 54]
and nutritional counseling [50]. Changes in glycemic profile are risk factors for cardiometabolic diseases [55];
this is the first study evaluating this parameter with nutritional intervention in PLWHA treated with ART [ 56].
However, this result for FPG could be attributed to differences in baseline values and not due to the
intervention.
In this RCT, there was an average reduction in WC close to being significant (p = 0.07). Similar results
were observed in another RCT of 0.9 cm at the end of follow-up [10]. The few studies that found a reduction
in WC were conducted with overweight PLWHA (BMI > 25 kg/m 2) [50,54] while in the present study, the BMI
at baseline was within the normal range. In the individualized dietary prescription group, there was a
reduction of 1.74 cm in WC, in contrast to an observational study that found an increase in WC in PLWHA
treated with ART [51]. This reduction observed in this RCT may be important in the long term to prevent
Nutrients 2020, 12, 2970 13 of 18

abdominal obesity. BMI remained stable in both groups. Another RCT with nutritional counseling observed a
significant reduction in BMI in the intervention group whilst this remained stable in the control [22].
One aspect that deserves special attention in RCTs is the clinical relevance of the results regardless of p-
values [57]. In the present study, although some outcomes did not show statistically significant reductions,
− −
they are worth mentioning. For example, the reductions in TC (−9.4 and −4.3 mg/dL), LDL ( 10.0 and 2.9
− −
mg/dL) and TG ( 27.5 and 21.4 mg/dL) and increases in HDL (1.8 and 2.8 mg/dL) observed in the
individualized dietary prescription and nutritional counseling group, respectively. Overall, in the
individualized dietary prescription group, the reductions were slightly more expressive, so the prescription of
an individualized food plan may contribute to improvements in LDL, TC, and HDL levels in PLWHA treated
with ART.
An important feature of this RCT was the application of multiple linear regression analysis with dummy
variables, allowing the identification of changes in the effectiveness of treatment in groups of patients with
distinct characteristics. In the individualized dietary prescription group, an even greater effectiveness of
treatment with significant reductions were observed in some patients: LDL (−24.8 mg/dL) among those with
brown/black skin color, BMI in those treated with ART longer than three years, and SBP (−12.2 mmHg) in
females, while for the other patients, there was no significant reduction in these cardiometabolic
parameters. The DBP that already had a significant reduction of 3.4 mmHg was further reduced in those
−
treated with PI when compared to other antiretroviral drugs, reaching 9.8 mmHg.
Some of our results showed significant worsening in the outcomes due to intervention in the nutritional
counseling group. For example, there were increases in TG values (12.6 mg/dL) among those aged 40 and
older, an increase in WC (1.5 cm) for those with brown/black skin color, reduction in HDL (−4.6 mg/dL) for
patients in the 4th quartile of income and, finally, a reduction in SBP of only 0.3 mmHg among those treated
with ART longer than one year, which is considerably lower than other patients who had a reduction of 5.2
mmHg. This type of statistical approach allowed us to better understand the clinical outcomes based on the
fact that participants’ individual characteristics may increase or even reduce the effectiveness of the
intervention. Therefore, the analytical approach adopted in this study that accounted for how subgroups
influence on the outcomes is a breakthrough not only in the RCT field but also in therapeutic approaches in
clinical practice.

5. Limitations and Strengths

One possible limitation of this study was the lack of double-blindness, due to the kind of treatment
approach [58]. For all types of behavioral interventions, such as physical activity and nutritional and
psychological treatments, it is difficult to conduct a blind study because of the nature of the intervention,
i.e., the participants know what is going on [58]. However, we tried to minimize such a limitation by using
some strategies to prevent information exchange between groups, such as avoiding the contact between the
intervention groups through different appointment schedules. Another potential limitation of our study
could be attributed to the lack of a control group with no intervention. However, such a control group would
not be approved by the ethics committee. The follow-up losses of both groups are similar and approximately
20%, which is expected in clinical trials.
Compliance to nutritional treatment is a subjective aspect difficult to analyze. Therefore, in our study,
having only one dietitian with expertise was a good approach due to its good quality. In nutritional
intervention studies, the dimension of adherence to dietary treatment is complex, and there is no method or
instrument that could be applied properly to all the objectives and studies [59].
Regarding the clinical relevance [57] of our findings, we were able to highlight that an individualized
dietary prescription could be a more appropriate and effective approach in reducing cardiometabolic risk
factors in PLWHA than only nutritional counseling. In other words, in an individualized dietary prescription,
the biochemical individuality could be taken into consideration.
Nutrients 2020, 12, 2970 14 of 18

We recommend that future RCTs are developed on this topic and with subgroup analyses, such as the one
carried out in the present study, since it is important to identify whether other variables can interfere with or
modify the effectiveness of interventions.
It is known that, globally, the ambulatory care settings for HIV/AIDS in most cases do not include a
registered dietitian, and nurses or physicians usually give a brief general nutritional orientation, if given.
Some ambulatory care units just have one nutritionist to attend many patients. Therefore, if a general
orientation, such as the one we had in one of the arms of our intervention, provides similar results to the
diet prescription arm, this finding could be used to justify its use to help more patients. We showed that the
general orientation had good results, but the individualized diet prescription demonstrated better results in
reducing cardiometabolic risk factors. Our results are relevant in highlighting the relevance of nutritional
treatments to reduce cardiometabolic risk factors. As the compliance was not different between the groups,
the results demonstrate the effectiveness of nutritional intervention.

6. Conclusions
This RCT demonstrated the effectiveness of both nutritional interventions in reducing some
cardiometabolic risk factors. However, the prescription of an individualized dietary plan was clinically more
effective in reducing several cardiometabolic risk factors in PLWHA treated with ART, particularly DBP, FPG,
TC, HDL, and the primary outcome LDL.

Author Contributions: Conceptualization, E.A.S., M.O.F. and A.S.e.A.d.C.S.; methodology, E.A.S., M.O.F.,
A.S.e.A.d.C.S., M.N. and C.d.O.; validation, E.A.S., M.O.F., A.S.e.A.d.C.S., M.N. and C.d.O.; formal analysis, E.A.S., M.O.F.
and A.S.e.A.d.C.S.; investigation, E.A.S., M.O.F., A.S.e.A.d.C.S. and M.N.; writing—original draft preparation, E.A.S.,
M.O.F., A.S.e.A.d.C.S., M.N. and C.d.O.; writing—review and editing, E.A.S., M.O.F., A.S.e.A.d.C.S., M.N. and C.d.O.;
visualization, E.A.S., M.O.F., A.S.e.A.d.C.S., M.N. and C.O.; funding acquisition, E.A.S. and C.d.O. Principal investigator,
E.A.S. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by the National Council for Scientific and Technological Development (CNPq), Brasilia,
Federal District and the Research Support Foundation of the State of Goiás (FAPEG), Goiânia, Goiás. Moreover, Cesar de
Oliveira is supported by the Economic and Social Research Council (grant ES/T008822/1).
Conflicts of Interest: The authors declare no conflict of interest.
Declaration: The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study
being reported. The reporting of this work is compliant with CONSORT guidelines. The lead author affirms that no
important aspects of the study have been omitted and that any discrepancies from the study as planned
(ClinicalTrials.gov NCT02180035) have been explained.

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