1 / 95

Long Term Complications of Treatment in Children

Long Term Complications of Treatment in Children. By Kulkanya Chokephaibukit , MD Professor of Pediatrics Faculty of Medicine Siriraj Hospital Mahidol University, Bangkok, Thailand. Lecture at HIVNAT 25 July 2013. HIV is an acceptable virus to live with!.

mulan
Download Presentation

Long Term Complications of Treatment in Children

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Long Term Complications of Treatment in Children By KulkanyaChokephaibukit, MD Professor of Pediatrics Faculty of Medicine Siriraj Hospital Mahidol University, Bangkok, Thailand Lecture at HIVNAT 25 July 2013

  2. HIV is an acceptable virus to live with! Emily, 7 year-old girl with ALL cured by using HIV gene therapy A disabled form of HIV deliver the gene to make chimeric antigen receptor T-cell (CTL019)of the patient that recognize the and destroy cancer cells

  3. Concerning Long Term Complications of Treatment in HIV-Infected Children and Adolescents • Lipodystrophy, esp. facial lipoatrophy • Metabolic complications that may result in cardiovascular diseases/coronary heart diseases/stroke, DM • Kidney dysfunction • Fractures risk/osteopenia/vitamin D deficiency • Neuro/psychiatric problems

  4. A 9 year-old boy with perinatal HIV Chief Complaint: Hyperpigmentation of neck and armpit for 2 years History: Maternal HIV without perinatal treatment Diagnosis of HIV infection by serology at 18 month-old , CD4: 256 cell/mm3 (12.39%) He was started on AZT+3TC (in 1998), then changed to HAART At 7 year-old, started to gain weight, very good appetite, and noticed hyperpigmentation Familial Hx: Mom died from AIDS. Live with grandparents, both hadDM

  5. The 9 year-old boy with dark neck for 2 years

  6. The 9 year-old boy with dark neck for 2 years

  7. Physical Examination: Wt 46.9 kg (>P97), Ht 140.8 cm (P97), 146% Ideal BW, BMI 23.9 kg/m2, WC76.5 cm, HC 73.7 cm W/H ratio 1.04 GA: loss of pad of fat/ lower limbs, dorsocervical hump Chest: gynecomastia GU: testes 5 cc, PH Tanner II Normal findings for heart, lungs, abdomen, and neuro examinations The 9 year-old boy with dark neck

  8. Hyperpigmentation of the neck and armpits, dorsocervical hump

  9. What is your diagnosis of his skin hyperpigmentation? A. genetic B. Acanthosis nigricans C. poor hygeine

  10. What is the common condition associated with this skin hyperpigmentation? A. Insulin resistance and diabetes B. Dyslipidemia C. Malignant melanoma

  11. Acanthosis nigricansA clue for IR 1.Krawczyk M. Pol Arch Med Wewn. Mar 2009;119(3):180-3. 2. Sadeghian G. J Dermatol. Apr 2009;36(4):209-12 • Hyperpigmented velvety macules and patches and progress to palpable plaques. Mostly observed at the intertriginous areas of the axilla, groin, and posterior neck • Causes: - Obesity, particularly with darker skin color. Children BMI>98th tile have AN in 62%.1 - Diabetes and Insulin resistance.2 - Polycystic ovarian syndrome - Malignancy: adenocarcinomas of the GI tract (70-90%), and others

  12. Problem Lists Obesity Acanthosis nigricans Lipodystrophy (mild facial lipoatrophy) FBS = 159mg/dl (Provisional DM) Metabolic syndrome?

  13. Lipodystrophy in HIV-infected children 1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004 3. Amaya RA. Pediatr Infect Dis J. 2002. 4. Sawawiboon N. Int J STD AIDS 2012, 5. Wangsomboonsiri W. CID 2010;50(4):597-604, 6.Likanonsakul S,AIDS Res Hum Retroviruses. 2012 Jul 9., 7.Alam NM. J Acquir Immune Defic Syndr. 2012; 59(3): 314–324 • Incidence vary 10-50%1-4 due to lack of consensus for definition • Associated with PI and stavudine • PI: Predominate with truncal obesity, buffalo hump, and less periheral lipoatrophy • d4T: Predominate with facial, associated with HLA-B*40015 and Fas gene6 • Likely to appear in early adolescence1,7

  14. Characteristics of Lipodystrophy from Protease Inhibitors • Fat gain on abdomen, breast, and dorsocervical hump • Fat loss from peripheral extremities • Fat gain in visceral organs

  15. Lipodystrophy from d4T Facial and peripheral lipoatrophy following >6 months of stavudine treatment, found in 38% of d4T Rx, occur around early adolescence Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501

  16. Body fat abnormality in HIV-infected children and adolescents: The difference of regions Study Population Lipoatrophy 23% Lipohypertrophy or combine 2.5%% No fat maldistribution 75% Europe (N= 426, LD = 42% Receiving PI 60%, Received d4T 10% Thailand, N=202, LD = 25% Receiving PI 41%, Received d4T 60% Alam NM. J Acquir Immune Defic Syndr. 2012 March 1; 59(3): 314–324 Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501

  17. Facial Lipoatrophy may improve after stopping d4T Facial lipoatrophy Is it reversible? Improvement found in 23%, at mean duration of 45 months after stopping d4T, around early adolescence Need to stop d4T before reaching adolescence Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501

  18. What about high FBS once? What would you do? A. Control sugar intake and repeat FBS B. Perform OGTT C. It’s mostly transient, repeat FBS in 6 months

  19. Interpretation of Fasting Blood Sugar Normal FBS Provisional DM Impaired FBS FBS 100 mg/dl 126 mg/dl

  20. Oral Glucose Challenge Test: Must be done in all cases of impair FBS Normal OGTT Provisional DM Impaired OGTT 2 hr PG 140 mg/dl 200 mg/dl

  21. Why do we need to worry about DM? A. A lot of treatment and complication of DM to follow, interrupt normal life B. DM increased risk of ART associated CVD C. Early intervention (exercise and metformin) may prevent or delayed DM and complications

  22. Symptoms of DM plus casual BG ≥200 mg/dL (polyuria, polydipsia, and unexplained weight loss) or FBS ≥126 mg/dL or 2-hr BS ≥200 mg/dL during an OGTT or HbA1C ≥ 6.5% Diagnosis of Diabetes Mellitus • Pre-diabetes • Impaired FBS 100-125 mg/dL • Impaired OGTT: 2 hr glucose 140-199 mg/dL • HbA1c 5.7-6.4% American Diabetes Association. Diabetes Care 2010

  23. Oral Glucose Tolerance Test 9 yo. boy with acanthosis nigricans Diagnosis: Impaired OGTT with hyperinsulinemia>>Pre-diabetes Normal fasting lipid profile

  24. Prevalence in adults 10-20% Increase prevalence in patients receiving HAART with lipodystrophy1 Incidence in children is much lower However, 19% of children receiving PI had impair OGTT2 Insulin Resistance and Type 2 Diabetes in HIV-Infected Children • 1.Vigouroux C. Diabetes & Metabolism 1999 • 2. Bitnun A. J Clin Endocrinol Metab 2005

  25. Classical T2DM risk factors Obesity (abdominal) Physical inactivity Genetic Family history Race Older age Dyslipidemia HIV-associated risk factors Peripheral lipoatrophy Increased liver or muscle fat Inflammatory cytokines Low testosterone Oxidant stress HCV infection PIs therapy Insulin Resistance and HIV

  26. How can we prevent DM in this patient? A. Diet and exercise B. Diet and exercise and metformin C. Control other factor: dyslipidemia

  27. Reduction in the Incidence of T2 DM with Lifestyle Intervention or Metformin 3234 patients with IFG or IGT Treatment; placebo, metformin, lifestyle-modification program Lifestyle-modification program: 7% weight loss and 150 mins of physical activity per week Average follow-up was 2.8 yr Exercise and Metformin can prevent DM Diabetes Prevention Program. N Engl J Med 2002:346:393-403

  28. Exercise and Metformin can prevent DM At 3 years 28.9% 21.7% 14.4% Lifestyle gr.: reduced the risk of converting to DM by 58% Metformin gr.: reduced the risk of converting to DM by 31% Incidence of DM in lifestyle gr.: 39% lower than metformin gr. Diabetes Prevention Program. N Engl J Med 2002:346:393-403

  29. None is approved in children Troglitazone (TRIPOD) (withdrawn due to rare hepatitis) Hispanic women with GDM  56% risk reduction Buchanan TA et al. Diabetes 2002 Acarbose (STOPP-NIDDM) Subject with IGT 32% decreased conversion to T2DM Chiasson JL et al. JAMA 2003 Xenical (XENDOS) Subject with BMI >29, lifestyle plus xenical vs placebo  37% risk reduction Torgerson JS et al. Diabetes care 2004 Drugs that may delay or prevent the development of Type2 DM

  30. A 9 Year-Old Boy with Perinatal HIV and Insulin-Resistance Treatment: Metformin (500) 1 tab oral bid Encourage healthy life style, exercise Continue ART: AZT/3TC/LPV/r Outcomes: 4 mo after treatment Wt 44.4 kg (-2 kg), Ht 142 cm, BMI 22 kg/m2 (-1.9) WC 76.2 cm (-0.3 cm)

  31. After 4 months of Metformin Rx and exercise: Improved hyperinsulinemia and BS OGTT 8/11/06 OGTT 12/1/07

  32. 6 Months later…He developed hyperlipidemia Fasting lipid profile

  33. NCEP Definition for Dyslipidemia in Children and Adults TG was not established by NCEP; a TG level of 125 mg/dL approximates the mean 95th percentile for TGs in boys and girls during childhood and adolescence.

  34. Why do we need to care about dyslipidemia? Should we just leave it for the adult doctors to take care of the business when the child grown-up! 1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004. 3. Amaya RA. Pediatr Infect Dis J. 2002 • It is an important risk factor for CVD in adults • Atherosclerosis starts in childhood, esp. if TC>200 and LDL-C >130 mg/dl • Very common, found 60%-80% in children receiving HAART, particularly PI1-3, found more in patients with lipodystrophy • Some PI cause less dyslipidemia: ATV, DRV

  35. Metabolic complications: >>Start from lipodystrophy, >>dyslipidemia, insulin resistance End up with cardiovascular diseases, stroke, DM

  36. Dyslipidemia found 40%-80% in children, associated with receiving PIand lipodystrophy1-3 Prevalence of Dyslipidemia in a European cohort of HIV-infected children and adolescents (N=426), 60% receiving PI4 Fasting Hypertriglyceridemia 66% Hyper-cholesterolemia 49% 45% 21% 28% 1% Glucose intolerance 5% 4% 1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004. 3. Amaya RA. Pediatr Infect Dis J. 2002, 4. Alam NM. J Acquir Immune DeficSyndr. 2012 March 1; 59(3): 314–324

  37. Frequency of abnormal lipid profile in Thai adolescentsSiriraj, Bangkok, 2013 49% receiving PI V. Poomlek. 7th IAS 2013, KL, MOPE047

  38. Risk of Myocardial Infarction in Patients Exposed to Specific Individual Antiretroviral Drugs : The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Worm SW. JID 2010;201:318-30.

  39. What else can we do other than even more encouraging lifestyle modification? A: Change ARV B: Start statin C. Start fibrate

  40. Treatment of dyslipidemia in children • Intervention in this patient: • Educate for life style modification: Low fat diet and exercise • Change LPV/r to ATV/r • Exercise at least 1 hr per day • Modified diet (<30% total fat and <7% of sat fat, <200 mg of cholesterol/day) • Statin only in those with persistent TC>200 mg/dl and LDL-C >130 mg/dl, not for < 8 yo, unknown long-term effect. • Fibrate for hypertriglyceridemia (>400 mg/dl) • ARV modification

  41. Lipid Changes at Week 48 with Baseline in PI Studies

  42. He started to be uneasy to take ARV **Once daily regimen Fasting Blood Sugar : 138mg/dl Cholesterol 155 mg/dl Triglyceride 159 mg/dl LDL 74 mg/dl HDL 50 mg/dl

  43. Diet education for dyslipidemia High Cholesterol Diet High Triglyceride Diet

  44. Diabetic diet education

  45. 5 Years after starting treatment And became a teenager Follow-up • FBS 400 mg/dl • HbA1C 13.8 % Dx: DM Start Insulin SC Does he meet the criteria for metabolic syndrome? …..Yes or No He becomes an uneasy adolescent and start to have poor compliance to metformin and diet and weight control - He continue to gain more weight BP: 130/90 mmHg TG = 202 mg/dl, HDL 52 mg/dl, Cholesterol 224 mg/dL

  46. Metabolic Syndrome A Cluster of Abdominal obesity Increased triglyceride levels Decreased HDL-cholesterol levels Hyperglycemia Hypertension A meta-analysis of the prospective studies has shown that the presence of metabolic syndrome increases the risk of Type2 DM and CVD Galassi A. Am J Med. 2006

  47. Metabolic Syndrome in children and adolescents: The clusters of metabolic risk factors (International Diabetes Federation) Presence of metabolic syndrome increases risk of - CVD (RR 1.53; 1.26-1.87) - CHD(RR 1.52; 1.37-1.69) - Stroke (RR 1.76; 1.37-2.25). Galassi A. Am J Med 2006;119:812-9

  48. International Diabetes Federation (IDF) Criteria for MS in Children Central obesity plus any two of other criteria Zimmet P et al on Behalf of the International Diabetes Federation Task Force on Epidemiology and Prevention of Diabetes. Lancet 2007:369:2059-2061

More Related