Efficacy of Tamarindus Indica Fruit Juice in Optimizing Cardiometabolic Health of Patients Living With HIV and Elevated Triglycerides
Phase: NA
Conditions: Cardiometabolic Syndrome, Dyslipidemias, Hypertension
Sponsor: KU Leuven

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Efficacy of Tamarindus indica fruit juice in optimizing cardiometabolic health of 
patients living with HIV and elevated triglycerides: A study protocol. 
 
Tonny Kiyimba1,2, Fred Kigozi3, Michael Bamuwamye1, Peter Yiga2, Katrine Nakatudde3, 
Winnie Nabbanja3, Patrick Ogwok1, Bart Van der Schueren2,4, Christophe Matthys2,4*.  
1 Department of Food Science and Technology, Kyambogo University, Kampala, Uganda 
2 Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, 
KU Leuven, Leuven, Belgium 
3 Nutrition unit, Department of Health Sciences, School of Applied Sciences, Mildmay Institute     
of Health Sciences, Kampala, Uganda  
4Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium 
*Corresponding author; Christophe.matthys@uzleuven.be 
 
1. Introduction 
1.1 Background 
Suboptimal cardiometabolic health is on a disproportional rise in Low- and Middle-Income 
Countries (LMICs). In sub-Saharan Africa (SSA), cardiometabolic dysfunction is being 
exacerbated by the ongoing nutrition transition, that has seen a change from traditional diets to 
fast and ultra processed foods rich in sugar, fats, and salt coupled by low physical activity (1). 
Similarly, chronic inflammatory diseases such as HIV can aggravate cardiometabolic risks (2). 
HIV aetiology and Antiretroviral Therapy (ART) have been shown to exacerbate metabolic 
syndrome. Although the pathophysiology remains rather elusive, HIV triggers glucose 
metabolism dysregulation and dyslipidaemia. In part, this is linked to the inflammation 
triggered by viral infection. The virus triggers chronic activation of the innate immune system 
with excessive production of inflammatory cytokines. These inflammatory mediators increase 
the risk of atherosclerosis and insulin resistance (2). Our recent study among people living with 
HIV (PLWH) under community-based HIV care model in Uganda revealed a high prevalence 
of metabolic syndrome (28%), central obesity (44.5%), raised fasting blood glucose (49.6%), 
hypertriglyceridemia (26.4%), low HDL-c (56.7%), and high blood pressure (31.5%). This 
cardiometabolic dysfunction is compounded by low quality carbohydrate-based diets devoid 
of fruits and vegetables (3). Fruits and vegetables are the bedrock of a healthy diet (4, 5). 
However, although WHO recommends a daily intake of at least 5 servings a day (6), in our 

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study the average intake of fruits and vegetables was just 1.5 servings and a low polyphenol 
intake (212 mg) (3). 
Beyond conventional nutrients, fruits and vegetables have ubiquitous amounts of bioactive 
components including polyphenols, alkaloids, saponins, and terpenes and terpenoids, with 
polyphenols being the most ubiquitous of all. Dietary polyphenols are a diverse category of 
secondary plant metabolites that represent the largest group of naturally occurring antioxidants 
with cardioprotective benefits (7-9). A daily 5 servings intake of fruits and vegetables coincides 
with 500-1000 mg of total polyphenols, a threshold that is considered beneficial for 
cardiometabolic homeostasis (10). Our recent meta-analysis demonstrated that an average 
intake of 780 mg/d of total polyphenols significantly reduced blood pressure, total cholesterol, 
triglycerides, and improved vascular function (11). The (poly)phenolic composition of fruits 
and vegetables can vary considerably according to the region of growth among other factors 
(9, 12). For example, Africa’s Indigenous Fruits and Vegetables (IFV) have been shown to 
contain high concentrations of polyphenols (13, 14). Our recent inventory study of Uganda’s 
IFV with purported cardiometabolic benefits, highlighted the popularity of Tamarindus indica 
as a local adjuvant therapy for cardiometabolic risks among Ugandan communities (15). The 
study also revealed that the polyphenol composition of T. indica is superior in 4755mg/100g 
FW in relation to other IFV identified. 
T. indica, is a leguminous tree belonging to the family Fabaceae with a wide range of bioactive 
constituents in varying levels- the highest being polyphenols followed by alkaloids, saponins, 
and terpenoids in that order (16). The principal flavonoids in T. indica fruit pulp are composed 
of flavanols especially the oligomeric procyanidins and their monomers- epicatechins and 
catechins (17, 18). Recent dietary guidelines for bioactives recommend a daily intake of 400-
600 mg of flavanols for cardiometabolic protection (19) while the European Food Safety 
Authority (EFSA) recommends that 200 mg/d intake of cocoa flavanols is important for 
vascular homeostasis (20). Elsewhere, the COSMOS study showed that an intake of 500 mg/d 
of flavanols averts 27% of CVD mortality with significant reduction in CVD events (21). 
Flavanol increases the endothelial production and bioavailability of nitric oxide, a signalling 
molecule for endothelial function (20) .  
A potential mechanism of action by which polyphenols confer hypotensive effects is by 
increasing the bioavailability of nitric oxide (NO) and upregulating endothelial NO-synthase 
activity. NO is a potent vasodilator that reduces blood pressure. Additionally, flavonoids 

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especially flavanols may block angiotensin converting enzyme (ACE) activity, reducing blood 
pressure. In fact, flavanols, anthocyanins, phenolic acids, tannins, and resveratrol have been 
identified as green ACE inhibitors (11). 
Although the benefits of the community-based HIV care model in the resource limited HIV 
management settings are well documented, in Uganda, the lack of dietary interventions 
promoting cardiometabolic health could obscure such benefits (22-24). Lifestyle modifications 
such as programmed physical activity, weight loss, and dietary adjustments are indispensable 
to optimal cardiometabolic health (25, 26). However, the existence of a health-beauty paradox 
in SSA could thwart such interventions premised on maintaining a healthy body weight. The 
health-beauty paradox is a socio-cultural positive perception where a large body size is 
construed as a sign of prosperity and freedom from HIV (27). Moreover, dietary approaches 
that aim to add a healthy food portion on to one’s habitual diet rather than completely changing 
their menu are by far more culturally diffusible (28). Therefore, we aim to evaluate the efficacy 
of T. indica fruit juice (added to patients’ usual diets) on selected cardiometabolic risk markers 
of PLWH under the community-based HIV care model in Uganda in a proof-of-concept clinical 
trial. Evidence could lead to the concomitant use of such food products as adjuvant therapies 
in the secondary prevention of cardiometabolic risks. 
1.2. Hypotheses 
The hypotheses are: 
H1: Consumption of T. indica fruit juice will result into an overall improvement in 
cardiometabolic (vascular function, blood pressure, glycaemic, and lipidemic) response. 
H2: There will be differences in the dose-response relationship in cardiometabolic control 
following the intake of increasing doses of polyphenols in T. indica fruit juice. 
2. Materials and Methods 
2.1.1 Intervention food materials 
Two blinded juice prototypes of 10% and 30% fruit pulp packaged in amber bottles each 
consisting of 300mls will be supplied by the Uganda Natural Chemotherapeutics Research 
Institute. The chemical and phytochemical characteristics of the test juice are presented in table 
1. 
 

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Table 1: Chemical and phytochemical characteristics of Tamarindus indica fruits juice 
Fruit juice 
prototypes 
(pulp %) 
TPC (GAE, 
mg/100ml) 
 TFC (RE, 
mg/100ml) 
 TT (GAE, 
mg/100ml) 
Alkaloids 
(%) 
Brix Ph 
 TTA (g of 
tartaric 
acid/100ml) 
Antioxidant 
potential, 
IC50, µL 
10% 
8.30 
6.75 
8.30 
0.34 
6.80 3.28 
0.35 
36.71 
30% 
26.36 
12.29 
10.17 
0.44 
6.80 2.89 
0.95 
37.46 
TPC, Total Polyphenols Content; TFC, Total Flavonoids Content; TT, Total Tannins; TTA, Titratable acidity 
2.2 Study design and participants  
This is a single centre, 2-arm, 4 weeks randomised, double-blinded parallel trial with equal 
allocation ratios (1:1). We will follow the Consolidated Standards of Reporting Trials 
(CONSORT) recommendations for randomized trials (32). Participants will be PLWH (30-60 
years) managed under the community-based model (Community Drug Distribution Points-
CDDPs) in Wakiso district, central Uganda. The district encircles Kampala, Uganda's capital 
city with an estimated population of over 2.9 million people. The district has the highest 
prevalence (10%) of HIV in Uganda. Over 3,801 PLWH are currently receiving the HIV care 
from CDDPs in Wakiso District (33). The study inclusion and exclusion criteria are presented 
in Table 2. The study will be announced during the drug refill days and interested patients will 
be provided with more information about the study before obtaining their consent to participate. 
Demographic and medical information will be collected from all consented patients,  
The study participants will be randomly allocated to consume twice-daily 300 mL of either 
10% or 30% pulp of T. indica fruit juice, figure 1. Both participants and the study team will be 
blinded to the intervention materials. Measurements will be performed at three different 
timelines: 1) Baseline, 2) Week two of the study, and 3) Endline (week four of the study). 
Compliance to the study protocol will be confirmed by weekly telephone inquiries, and by 
counting the returned empty juice bottles or unused study products at each follow-up visit. 
Participants will be asked to maintain their habitual dietary regimen. 
Any reported unusual gastrointestinal side effects, including abdominal pain/cramps, 
heartburn, stomach acid/reflux, nausea, vomiting, abdominal rumbling, bloating, belching, 
excess gas/wind, stool type, etc, during the study will be recorded. Patients will be encouraged 
to contact a study staff by phone or e-mail if they experience any adverse health-related impacts 
of the interventions. In the case of T. indica fruit juice intolerance, patients will be excluded.  
 
 

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Randomisation and blinding 
A biostatistician of Mildmay hospital will develop computer-generated sequence to randomly 
allocate participants to each of the two study arms, as shown in figure 1. The biostatistician 
responsible for generating the allocation sequences will not have any study-related tasks, for 
example, inclusion or examination of participants. The two juice prototypes will be blinded by 
assigning a secret code to each of the intervention products. As such, blinding of the 
investigators and participants will be undertaken to ensure a double-blind intervention. 
Moreover, the statistical analyses of the main endpoints will be done before breaking the 
intervention product concealment. 
 
 
 
BP, Blood Pressure; BC, Body composition; FBG, Fasting Blood Glucose; TG, Triglycerides; Tc, Total cholesterol; PA, 
Physical Activity; PWV, Pulse Wave Velocity; WC, waist circumference.  
 
Figure 1: Schematic overview of the study protocol. 
 
 
 
 
 
 
 
 
 
 

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Table 2: Eligibility criteria for study participants 
Inclusion criteria 
Exclusion criteria 
Triglycerides ≥150 mg/dL 
Taking dietary supplements 
TLD regimen (ART) for ≥12 months  
TB co-infection, renal failure disease, liver 
cirrhosis, chronic pancreatitis 
95% ART adherence in last 6 months1 
Pregnancy and Lactation or regular sport activity 
Virally suppressed (most recent results viral load 
suppressed within the last 12 months)1 
Parallel participation in another clinical trial 
PLWH aged ≥30≤60 years. 
No plans to change location in the next 6 months 
On treatment for; dyslipidaemia, hypertension or 
diabetes and oral hypoglycaemic drugs 
 
Very low blood pressure (< 90/50 mmHg) 
Not willing to consent or unable to consent 
ART, Antiretroviral Therapy; DBP, Diastolic blood pressure; FGD, Focus group discussion; SBP, systolic blood pressure; 
TLD, Tenofovir Lamivudine Dolutegravir; WC, waist circumference.  
1In line with the national guidelines for community drug distribution points (Community care model for HIV), WHO stages 1 
or 2 (34). 
 
2.3.1 Study outcomes  
The primary endpoint will be changes in Triglycerides (TG). Secondary outcomes will include 
changes in fasting blood glucose and plasma levels of lipids, and parameters of vascular 
function, Table 3. 
 
Table 3: Study outcome measures 
Primary outcome measures 
Secondary outcome measures 
Exploratory outcomes 
Triglycerides [mg/dL] 
PWV [m/s], Blood pressure [mmHg] 
BMI [kg/m2] 
 
Fasting Blood glucose [mg/dL] 
Fat mass composition  
Waist circumference [cm] 
 
HDL-c, LDL-c, Total cholesterol [mg/dL]  
 
AIx (%), MAP 
 
BMI, Body Mass Index; PWV, Pulse Wave Velocity; HDL-c, High Density Lipoproteins; LDL-c, Low Density Lipoproteins; 
AIx, Augmentation Index; MAP, Mean Arterial Pressure  
 
2.4 Protocols for measuring study outcomes. 
2.4.1 Biochemical Measurements  
CardioChek Plus will be used to assess fasting blood glucose and lipid profile (total cholesterol, 
HDL-c, LDL-c, and triglycerides). It is an on-site test which gives results in as little as 90 
seconds. The CardioChek plus is patient friendly in that it requires a fingerstick blood sampling 

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of 15 to 40 μL. Participant safety is guaranteed; the trained laboratory technician handling the 
testing will sanitize and wear cloves while doing the test, the participants finger (middle or ring 
finger) will be cleansed with an alcohol wipe for at least 30 seconds and the stick will always 
be on the side of the finger rather than the tip. The testing will be performed by trained 
laboratory technician. Participants will be requested to fast overnight and not to indulge in 
exercise in the morning. To ensure this, tests will be carried out early morning before breakfast. 
 
2.4.2 Parameters of vascular function  
2.4.2.1 Pulse wave velocity, Mean arterial Pressure, and Augmentation Index 
Increased arterial stiffness, measured non-invasively by aortic pulse wave velocity (PWV), is 
one of the earliest detectable manifestations of adverse structural and functional changes of the 
vessel wall (35). Aortic PWV will be estimated twice in the supine position on the right upper 
arm, using the validated Arteriograph device (TensioMed, Budapest, Hungary) (36). The 
Arteriograph is an operator-independent, non-invasive device that uses an oscillometric 
occlusive technique to estimate the aortic PWV and AIx. In short, after two conventional BP 
measurements, the Arteriograph produces a cuff pressure over the brachial artery that is 35 
mmHg in excess of the systolic blood pressure measured. This suprasystolic pressure is used 
to analyse the pulse wave. To calculate the PWV, the distance from the jugulum to the 
symphysis is measured in a straight line using a tape measure, as a surrogate measure of the 
aortic length, and multiplied by two. The result is then divided by the difference in time 
between the beginning of the first wave and the beginning of the second (reflected) wave, 
resulting in the PWV in meters per second (m/s) (36, 37). The two conventional BP 
measurements of the Arteriograph will be used to calculate the mean arterial pressure (MAP). 
The AIx corresponds to the pressure difference (amplitude difference; P1-P2) between the first 
and second wave in relation to the pulse pressure (PP). The Arteriograph calculates the AIx on 
the basis of the formula, AIx% = [(P2-P1)/PP] *100 and thus provides the brachial AIx without 
applying a transfer function (37). In order to standardize the measurement, we will use the 
protocol provided by the manufacturer. At the end of every examination day, data will be 
directly exported from the Arteriograph output into SPSS, preventing data-entry errors.  
2.4.2.2 Blood pressure 
Blood pressure will be measured using blood pressure monitor – Seca b12. Blood pressure 
measurements will be taken on the left arm with the participant in a sitting position (after a 
five-minute rest in sitting position). Two readings will be taken at least one minute apart and 
the mean of the last two readings will be taken as the final blood pressure. In case of there’s 

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more than a 5-mm Hg difference between the first and second readings, additional readings 
will be obtained and then the mean value of these multiple readings will be used (38). 
2.4.3 Anthropometrics  
Height will be taken to the nearest 0.1 cm using a portable stadiometer. Weight will be 
measured to the nearest 0.1 kg using the Seca 874 dr weighing scale. Participants will remove 
shoes and heavy clothing (jackets) and pocket items before measurements. Weight and height 
measurements will be used to calculate BMI (kg/m2). Waist circumference (to the nearest 0.5 
cm) will be measured using a non-stretchable standard tape measure (gulick measuring tape). 
The waist measurement will be taken at the level of the iliac crest with the participant standing, 
at the end of gentle expiration (39).  
2.4.4 Body composition measurement  
Body composition will be measured using Bodystat 1500 lite touch. This equipment uses the 
scientifically validated principle of bio-electrical impedance analysis, to measure body 
composition parameters namely, fat, lean weight, optimal total body weight range and body 
water levels, is instantly displayed on the screen of the Bodystat 1500 lite touch. The 
measurement is not recommended after strenuous exercise. The body would have lost excessive 
fluid through sweat, and an abnormally low fluid level would increase the impedance 
measurement resulting in an artificially higher percent fat than would normally be the case. 
Therefore, participants will be advised to avoid strenuous activities on the day of measurement. 
To ensure this, tests will be carried out early morning before breakfast. 
 
5. Other measurements 
5.1 Dietary intake  
Data on dietary intake will be collected by a non-consecutive two day 24-hour dietary recall 
method (40). The recall will be interactive to allow for estimation of food quantities and sizes. 
The participants will be thoroughly probed to ensure that no foods consumed are forgotten. The 
time of food consumption will also be recorded. Participants will estimate their food portion 
sizes using a photographic atlas. The atlas utilizes photos of estimated food portions and their 
corresponding weight in grams.  
 
 5.2 Physical activity 
Physical activity will be measured using the validated short form of the international physical 
activity questionnaire (41). 

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6. Statistical analysis 
This is a proof-of-concept (no power calculation). The study will use a pragmatic sample size. 
Intention to treat analysis will be conducted. Continuous variables will be presented as mean 
and standard deviation. Student t-test will be applied to compare means of endpoints between 
patient groups. Outcome variables will be checked for normality and transformed where 
necessary. To account for any missing data, analyses will be conducted using linear mixed 
models. Analysis will be performed using the Statistical Package for the Social Science (SPSS) 
software version 22 (IBM Corp, Armonk, NY, USA). A p-value of <0.05 will be used for 
statistical significance.  
 
7. Ethics and regulatory approvals 
All study procedures will be conducted in accordance with the Helsinki Declaration and the 
study protocol will be registered in a public database (ClinicalTrials.gov). Research approval 
and permit has been sought and granted by the research ethics committee of Clarke 
International University and Uganda National Council of Science and Technology. All willing 
participants will be asked to voluntarily sign an informed consent form at the point of 
recruitment. The research team will protect the data from disclosure outside the research 
according to the terms of the research protocol and the informed consent document. The 
investigator will treat all information and data of participants as confidential and shall not 
disclose such information to any third parties or use such information for any purpose other 
than the performance of the study. The subject’s name or other identifiers will be stored 
separately from their research data and replaced with a unique code to create a new identity for 
the participant. It is anticipated that the results of the study will be presented at national and 
international conference or published in an international peer reviewed journal. Authorship to 
publications will be determined in accordance with the requirements published by the 
International Committee of Medical Journal Editors and in accordance with the requirements 
of the respective medical journal. Each participant will be offered a healthy snack and also 
compensated USD 8 each visit to cater for transport. 
8. Direct access to source data and documents  
 
The investigator(s) will permit study related monitoring, ethical committee review and 
regulatory inspections (where appropriate) by providing direct access to source data and other 
documents. 
 

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9. Individual Participant Data (IPD) Sharing Statement 
Plan to Share IPD: 
Yes 
Plan Description: 
For all the data generated during the course of this study, we will 
follow the prevailing standards and guidelines in documenting and 
depositing data sets. 
The research team will disseminate results from this research through 
presentations at public lectures, scientific institutions and meetings, 
and/or publication in major journals. Regarding data sharing, 
International Committee of Medical Journal Editors recommendations 
will be followed. 
Individual deidentified participant data will be shared. In particular, 
individual participant data that underlie the results reported in our 
articles, after deindentification (text, tables, figures and appendices). 
Supporting Materials: Study Protocol 
Informed Consent Form (ICF) 
Analytic Code 
Time Frame: 
Data will become available from 9-36 months after the publication of 
the study-results by the research team. 
Access Criteria: 
Data will only be shared with investigators whose proposed use of the 
data has been approved by an independent review committee 
identified for this purpose. Proposals should be directed to Prof. 
Christophe Matthys (Christophe.matthys@uzleuven.be). To gain 
access, data requestors will need to sign a data access agreement. 
 
10. Withdrawal of participants  
Participants can withdraw from the study at any time for any reason if they wish to do so.  
11. Funding 
The research is funded by the Belgian Directorate General for Development Cooperation and 
Humanitarian Aid (DGD), an initiative implemented by VLIR-UOS. 
 
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