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High prevalence of PLIN gene & Metabolic risk factors among Children initiating Antiretroviral therapy in south India P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani, R. Srinivasan, G. Sanjeeva, P. Gangadevi, E. Suresh, C. Chandrasekar, C. Wanke, S. Swaminathan National Institute for Research in Tuberculosis (ICMR), India

P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

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High prevalence of PLIN gene & Metabolic risk factors among Children initiating Antiretroviral therapy in south India. P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani, R. Srinivasan, G. Sanjeeva, P. Gangadevi, E. Suresh, C. Chandrasekar, C. Wanke, S. Swaminathan - PowerPoint PPT Presentation

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Page 1: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

High prevalence of PLIN gene & Metabolic risk factors among

Children initiating Antiretroviral therapy in south India

P. Chandrasekaran, A. Shet, K. Ramesh, P.K.Bhavani, R. Srinivasan, G. Sanjeeva, P. Gangadevi, E. Suresh,

C. Chandrasekar, C. Wanke, S. SwaminathanNational Institute for Research in Tuberculosis (ICMR), India

Page 2: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Introduction• Antiretroviral therapy

– Overall reduction of morbidity & mortality – lead to development of Metabolic syndrome /

HIV Associated Lipodystrophy Syndrome (HALS)

• Similar exposure to drugs, diet, socioeconomic status, not every child on ART develops HALS

• Host Genetic factors

Page 3: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Host Genetic factors & HALS• Polymorphisms in APOA5

APOC3, APOE & CETP• Perilipin gene (PLIN), major

protein coating intracellular lipid droplets , modulates adipocyte lipolysis

Arnedoa M et al.. Pharmacogenetics and Genomics 2007, Ordovas JM et al. Curr Opin Lipidol 2007; 18: 152Qi L et al. Clin Genet 2004;

• Minor allele at PLIN 11482 (G>A) is associated with higher risk of metabolic syndrome

- Higher TGL / Lower HDL-c / Higher insulin resistance• No Indian Studies

Page 4: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

India “HALS” study• Prospective study • To determine the incidence

& risk factors of dyslipidemia, insulin resistance & body shape changes

• Children 2-12 years, initiating ART (2NRTI + 1 NNRTI)

• NIRT, Chennai & SJRI, B’lore

Page 5: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Objectives

• To assess the baseline risk factors of metabolic syndrome, namely blood lipid profile, glucose, insulin resistance and waist: hip ratio, among children before they initiate first-line antiretroviral therapy

• To look for the presence of polymorphisms of specific gene PLIN - associated with metabolic syndrome - in these children

Page 6: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Data collection• Anthropometry, body circumferences & skinfold

thickness • 24-hour dietary recall and Food security • Fasting blood for Serum lipids, Glucose, Insulin, high-

sensitivity C-reactive protein (hs-CRP) • CD4 cell count & HIV-1 viral load • PLIN Gene polymorphisms RT- PCR• Homeostatic model assessment-Insulin resistance

(HOMA-IR) estimated using the formula [fasting glucose (mg/dL) X insulin (uU/mL)]/405

Page 7: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Study population

• 218 Children living with HIV infection – mean age: 8 + 3 years (2-12years)– mean body weight : 18 + 6 kgs– mean CD4%: 15% (1-54%)– median viral load : 179,136 copies/ml (46,090 – 574,494)

• 60% WHO Clinical Stage III or above • 16% co-infected with Tuberculosis

Page 8: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Study population• 97% through Vertical Transmission

– Only 35% mothers diagnosed antenatal• 61% were vaccinated up-to-date

• 40% households food insecure– 15% in foster-care

• Triple drug therapy, with 2NRTI + 1NNRTI – Regimen containing d4T : 48 / AZT :154 / ABC 16

Page 9: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Nutritional IndicatorsNo. of Children

(n=218)Percentage

Stunting (HAZ < -2SD) 122 56%

Underweight (WAZ < -2SD) 129 59%

Wasting (WHZ < -2SD) 38 17%

• Stunting or chronic malnutrition reflects past shortage of food intake or chronic illness - negatively and irreversibly affects linear growth, organ growth & cognition

• Underweight – composite indicator of both past & present under nutrition (measure of MDG)

Page 10: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Risk Factors of Metabolic Syndrome 1. Fasting Blood Lipids

Parameters (mg/dl) Mean (SD) (n=218) Normal Range

Total Cholesterol 130 (35) 150-200

LDL-Cholesterol 78 (28) 100 – 129

HDL-cholesterol 29 (11) 40 - 60

Sr.Triglycerides 142 (71) 10 - 150

• Hypocholesterolemia seen in majority of CLHIV• 87% of children having low HDL-c• Serum Triglycerides > 150 mg/dl seen in 37% CLHIV• Waist: Hip ratio 0.96 (WNL)

Page 11: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Risk Factors of Metabolic Syndrome 2. Insulin Resistance

Blood Parameters Mean (SD) (n=218) Normal Range

Fasting Glucose 84.0 (14) 60 – 110Serum Insulin 8.2 (13) 5 – 20

C-reactive Protein 2.0 (3.1) <3.0 low riskHOMA-IR 1.8 (2.3) < 3.5

• HOMA-IR > 3.5 in 13% of children at baseline • hs-CRP of 3-10 mg/dl in 22%

- indicators of high risk for metabolic syndrome

Page 12: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

3a. PLIN Gene PolymorphismsPLIN 11482G>A (rs894160) (n=189)

Parameters GG (n=86)Mean (SD)

GA + AA (n=103)Mean (SD)

P value

Age (years) 7.2 (3) 7.5 (3) 0.42Weight (kgs) 17.9 (6) 17.8 (6) 0.95Waist circum. 52.4 (7) 52.4 (7) 0.99

Triglycerides (mg/dl) 132.5 (69) 156.2 (78) 0.03Tot. Cholesterol 129.1 (38) 127.3 (28) 0.71HDL-c (mg/dl) 28.3 (11) 28.2 (11) 0.99

• PLIN 11482 minor allele (GA+AA) associated with significant higher sr. triglycerides level at baseline

Page 13: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Discussion• Even before ART initiation, risk factors for

Metabolic syndrome seen in HIV-infected ART-naive children in South India

– serum triglycerides > 150mg/dl : 81 children (37%)– HDL-cholesterol < 40mg/dl: 189 children (87%)– HOMA-IR > 3.5 : 29 children (13%) – hs-CRP 3-10mg/dl : 22% of children

Page 14: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Discussion• In our cohort of CLHIV, minor allele A at PLIN4

11482G>A, which is associated with increased risk of MS, seen in 55% (103/189) of children – At baseline, among those with raised triglycerides,

68% (50/74) had minor allele A– Among those with normal TGL 46% (53/113) had

minor allele A at PLIN4 11482G>A

• PLIN 6209T>C, PLIN13041A>G did not find any association in our cohort

Page 15: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

Conclusion• Despite background of food insecurity and

malnutrition, substantial number of HIV-infected ART-naive children are at high risk for development of Metabolic Syndrome

• Given the relatively large number of carriers of genetic risk variants in this group, children with advanced disease need to be closely monitored for the development of MS, once ART is initiated

• Prevent long-term morbidities. Study is ongoing

Page 16: P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,

AcknowledgementsTufts University, Boston• Dr. Christine A Wanke,• Dr. Jose OrdovasSt. John’s Research Institute, B’lore• Dr. Anita ShetIndira Gandhi Hospital, Bangalore• Dr. GN Sanjeeva

Ro1 AI084390

• All study participants• ART centre Medical Officers