RESEARCH INTEREST: HIV TREATMENT OUTCOMES IN ADULTS PARTICULARLY RELATING TO BONE QUALITY AND BODY COMPOSITION

TITLE:  Mineral bone disease and body composition in HIV infected patients attending the adult ART clinic in Jos

Abstract:

The number of persons living with the human immunodeficiency virus (HIV) infection/ acquired immunodeficiency syndrome (AIDS) is greatest in the middle and low income countries where these individuals are now living longer with improved quality of life as a result of the introduction of HAART in their treatment over the years.  Uncommon complications of the disease and treatment are now being seen with improved survival of these individuals including the development of bone mineral density and body composition abnormalities. The consequences of these include osteoporosis, osteopenia with increased tendency to fractures and hence poor quality of life. Although the burden of HIV is in sub-Saharan Africa, there is largely a paucity of knowledge about bone health and body composition of HIV infected persons in our environment. We hypothesize that mineral bone health and body composition in HAART experienced and HAART naïve HIV- infected patients are similar to that of apparently healthy individuals in a comparative study. This study seeks to fill that knowledge gap and provide data that will inform management policies in this area.

Ethical Considerations: Ethical clearance will be obtained from the Ethics Committee of JUTH. A written informed consent will be obtained from the patients their decision to participate/decline and complete/ discontinue in the study would be duly respected without prejudice.

BUDGET:

Expenditure category	Unit cost (N)	Total cost (N)
Direct personnel cost-Research assistant	20,000 (x 10 months)	200,000
Sub-total personnel direct cost		200,000
Non-personnel direct cost
Laboratory analysis and consumables 1. Random blood sugar X 240 2. Serum Creatinine  X 240 3. Alkaline phosphatase (bone fraction) X 240 4. Serum calcium X 240 5. Serum Phosphate X 240 6. Serum lipids X 240 7. Urinalysis X 240 8. Vacutainer  X 3 packs 9. Vacutainer needles X 2 10. Universal Urine bottles X 250	500 500 500 500 500 2500 400 4000 1000 30	120,000 120,000 120,000 120,000 120,000 600,000 96,000 12,000 2,000 7,500
Sub- total Laboratory analysis and consumables		1,317,500
Equipment (QUS, OMRON BIA)	To be provided by the Investigator
Data management	100,000
Communication	100,000
Hand hygiene facilities	100,000
Publication cost	200,000
Sub-total non-personnel direct cost	1,817,000	1,817,000
Total Direct cost		200,000
Total cost		2,017,000

 

Project Narrative

When awarded with the research grant it will provide pilot data which will be invaluable in future grant application. It will provide experience in conducting research and when the data is well disseminated it would attract external collaborators for RO1 grants.

Research Plan

i. The aim of this study is to characterize the effects of HAART on mineral bone density and body composition of persons on treatment for HIV/AIDS.

ii. The specific objectives of the study include:

1. To determine the association of HIV/AIDS with abnormalities of bone mineral density in persons infected with HIV
2. To determine the association of HIV/AIDS with abnormalities of body composition in persons infected with HIV
3. To determine the association of HAART with abnormalities of bone mineral density and body composition in persons infected with HIV

iii. Background and significance:

The number persons living with the human immunodeficiency virus (HIV) infection/ acquired immunodeficiency syndrome (AIDS) is greatest in the middle and low income countries where these individuals are now living longer with improved quality of life as a result of the introduction of HAART in their treatment over the years.¹ However with improved survival, these individuals are now developing uncommon complications of the disease and treatment.² Several organ systems are affected by HIV or its treatment including the bones and body composition.³ It has been reported that HIV infected individuals are at a greater risk of developing low bone mineral density (BMD), principally osteopenia and osteoporosis, resulting in pains, body weakness and increased tendency for fractures.⁴ Body composition in HIV infected patients is affected primarily by the loss of lean body mass and also by combined antiretrovirals (cARVs) through fat redistribution.^5,6 

Although the burden of HIV is in sub-Saharan Africa, majority of these studies were carried out amongst Caucasians with very few reports in indigenous Africans. It is then unknown the quality of bones, body composition that HIV infected persons in our environment have. This study seeks to fill that knowledge gap and provide data that will inform management policies in this area.

 

iv. Methods:

This will be a cross sectional comparative study among HAART experienced (HIV positive individuals on HAARTfor at least 6 months), HAART naïve individuals (HIV positive but not yet on HAART) and HIV uninfected individuals18 years of age or older who meet the eligibility criteria; and provide written informed consent.  The study will span a period of eight months. The study will be conducted at the ambulatory HIV clinic of the Jos University Teaching Hospital which is supported by PEPFAR. This clinic has about 15,000 patients on enrolment with an average of 350 new enrollees every year.
 

Subjects

There will be two groups of HIV patients that will be enrolled (patients on HAART for a minimum of 6 months will serve as the cases while HIV infected patients who have never used HAART will serve as controls). An age and sex matched HIV uninfected individuals will serve as secondary controls.

Inclusion and exclusion criteria for HIV patients: All HIV patients between18 years and 60 years who are yet to commence HAART or who are on HAART for greater than six months will be included while those who used the following drugs within the last three months: corticosteroids, anti-cancer medications, anti-diabetic medications, ketoconazole, combined contraception pills and bisphosphonates will be excluded from the study. Also to be excluded are pregnant women, lactating mothers in the last one year,  those who have not used HAART for up to six months and those with a history of chronic kidney disease and or whose estimated glomerular filtration rate (eGFR) is less than 60ml/ml/1.73m².

Inclusion and exclusion criteria for controls: All individuals between 18 years and 60 years who test negative at the HCT outpost will be included in the study. The same exclusion criteria will apply to this group of controls.

Samples size: Given an estimated prevalence of osteopenia of 42.8% and 33% among   HAART experienced and HAART-naive HIV infected person, a minimum sample size of 60 HAART experienced and 60 HAART-naive HIV infected persons (total of 120) will be needed to achieve a power of 80% at 95% CI. A similar number of HIV-negative subjects matched for age and sex will be recruited as secondary controls.

Sampling Method: A non-probability sampling method will be employed in this study where every consecutive HAART naïve, HAART experienced patient and HIV negative individuals will be recruited till the minimum sample size is met.

Data Collection: An interviewer administered questionnaire will be used to collect data from all participants. Demographic and clinical information to be obtained from each subject include: age, sex, marital status, occupation, years of education, duration of HIV, type of ARVs, number of years on treatment, history of hypertension, diabetes or kidney disease; family history of hypertension, diabetes mellitus and kidney disease; chronic use of analgesics, use of alcohol, and smoking of cigarettes. Height and weight will be measured in meters and kilograms respectively using a stadiometer and weighing scale with the participants wearing light clothing with no head gear. Body mass index (BMI) was calculated using the Quetelet index.⁷ Blood pressure will be measured according standard guidelines.⁸

Body composition will be determined by bioelectrical impedance using OMRON Body Logic handheld  device while bone mineral density will be assessed by quantitative ultrasound (QUS), Achilles+ (Lunar Corporation, Madison, WI, USA) at the calcaneus, an alternative to the reference method (i.e. dual X-absorptiometry), often not available in resource-limited countries. ⁹ QUS uses high-frequency sound waves to evaluate bone properties and the heel is particularly favoured because of its high trabecular bone and its high metabolic turnover.

Urine samples will be tested for proteinuria using the Combi- 9 dipstix while venous blood will be obtained for serum creatinine, random blood glucose, alkaline phosphatase (bone fraction), serum calcium, and phosphate and serum lipids. Serum creatinine will be estimated using the kinetic enzymatic method and eGFR will be calculated using the CKD-EPI formula. CD4 T cell count and HIV-1 RNA viral load which are measured in the HIV positive subjects using Cyflow (Partec, Germany) and Roche Ampliclor (version 1.5, Brancburg, NJ, USA) machines respectively will be obtained from the patients’ record at the HIV clinic.

Outcome measures: 

1. A T-score of <-1.0 to ≥ -2.5 will be taken as low bone mass (Osteopenia) while a score of  

<-2.5 is osteoporosis. ¹⁰

2. Fat free mass (FFM) values outside the range of 78%-90% for men and 68%-80% for females will be taken as abnormal

3. For total body composition (TBC), values ≥40% for women will be regarded as obese while values <22% will be regarded as under-fat. Amongst the males, values ≥35% will be regarded as obese while <12% will be regarded under-fat.

Statistical Methods: Data will be analysed using Epi info version 7.2.0.1, (CDC, Atlanta GA) and Windows Excel statistical software. Continuous variables that are uniformly distributed would be expressed as means ± standard deviation and the skewed continuous as median with interquartile range (IQR), while categorical variables would be expressed as proportions. Results would be presented in figures and tables as appropriate. ANOVA or   student test would be used to compare group means where appropriate, while Chi-square test would be used to compare categorical variables.  The variables with a p value <0.25 on univariate analysis and other clinically relevant variables will be entered into a multiple Logistic regression models to determine the independent predictors of the primary endpoints. P values of <0.05 will be considered significant.

References:

1. World Health Organization. Global Health Observatory. Number of People (All Ages) Living with HIV 2013. Available from: Http:// www.who.int/gho/hiv/epidemic_status/cases_all/en/ (cited August 12, 2016)

2. Patel KK, Patel AK. Future Implications: Compliance and Failure with antiretroviral therapy. J Post Grad Med. 2006; 52 (33): 197

3. McDermott AY, Shevitz A, Knox T, Roubenoff R, Kehayias J, Gorbach S. Effect of highly active antiretroviral therapy on fat, lean, and bone mass in HIV-seropositive men and women. Am J Clin Nutr. 2001;74(5):679-686.

4. Arnsten JH, Freeman R, Ruth F, et al. Decreased bone mineral density and increased fracture risk in aging men with or at risk for HIV infection. AIDS. 2007;21:617–23

5. Ott M, Lembcke B, Fischer H, et al. Early changes of body composition in human immunodeficiency virus-infected patients: tetrapolar body impedance analysis indicates significant malnutrition. Am J Clin Nutr 1993; 57:15–9

6.  Grunfeld C, Saag M, Cofrancesco J Jr, et al. Regional adipose tissue measured by MRI over 5 years in HIV-infected and control participants indicates persistence of HIV-associated lipoatrophy. AIDS 2010; 24:1717–26.

7. Eknoyan G. Adolphe Quetelet (1796-1874): the average man and indices of obesity. Nephrol Dial Transplant 2007; 23:47-51

8. World Hypertension League. Measuring your blood pressure. Available at:

http://www.mco.edu/org/whl/bloodpre.html. Accessed October 1st 2016

9. Fantauzzi A, Floridia M, Ceci F, Cacciatore F, Vullo V, Mezzaroma I. Usefulness of calcaneal quantitative ultrasound stiffness for the evaluation of bone health in HIV-1-infected subjects: comparison with dual X-ray absorptiometry. HIV AIDS (Auckl). 2016 May 31;8:109-17. doi: 10.2147/HIV.S99904. eCollection 2016

10. Kanis JA, Melton LJ 3^rd, Christiansen C, Johnson CC, Khaltaev N. The diagnosis of Osteoporosis. J Bone Miner Res. 1994; 9: 1137-1141

 

Plan for Protection of Human Subjects

A written informed consent would be obtained from the patients. Patients with limited understanding of English would be adequately informed on the study in the language they understand best. The benefits to the patients will include determination of osteopenia, osteoporosis and abnormal fat distribution which will be addressed by counseling and drugs. Their decision to participate/decline and complete/ discontinue in the study would be duly respected without prejudice. Data would be de-identified and coded, the codes would be separately and securely stored from the main data and all information would be treated with utmost confidentiality.

Pending IRB Approval

Ethical clearance for the study will be obtained from the Ethics Committee of the Jos University Teaching Hospital.

Mentor: Prof Emmanuel I. Agaba, Department of Medicine, Jos University Teaching Hospital.

 Email: eiagaba@yahoo.com; 08037001392 (Previous grants)

Mentee: Dr. Esala E. Abene, Department of Medicine, Jos University Teaching Hospital.

 Email: eslaabene@yahoo.com; 08035699267

CAREER PATH: I am currently a Consultant Nephrologist with research interest in renal disease in adults. I envisage that in ten (10) years’ time I should be a Professor of General Internal Medicine and Nephrology.