* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download PowerPoint Template - HIV-NAT
Document related concepts
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! 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 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 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 had DM The 9 year-old boy with dark neck for 2 years Age %CD4 CD4 count VL ART 18 mo 12.39 256 - AZT+3TC 3Y 2.03 48 - d4T+ddI+EFV 4.5 Y 2.79 72 504,000 d4T+3TC+EFV M41L, D67N K101E, V179D 5.5 Y - - - AZT+3TC+IDV/ r 5.6 Y 3.04 137 <40 AZT+3TC+IDV/ r The 9 year-old boy with dark neck for 2 years Date %CD4 CD4 VL ART count 5.6 Y 3.04 137 <40 AZT+3TC+IDV/r 8.5 Y 19.63 930 - AZT+3TC+IDV/r 9Y 19.35 592 - AZT+3TC+LPV/r 9.5 Y 23.86 679 <40 AZT+3TC+LPV/r The 9 year-old boy with dark neck Physical Examination: • Wt 46.9 kg (>P97), Ht 140.8 cm (P97), 146% Ideal BW, BMI 23.9 kg/m2, WC 76.5 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 Hyperpigmentation of the neck and armpits, dorsocervical hump What is your diagnosis of his skin hyperpigmentation? A. genetic B. Acanthosis nigricans C. poor hygeine What is the common condition associated with this skin hyperpigmentation? A. Insulin resistance and diabetes B. Dyslipidemia C. Malignant melanoma Acanthosis nigricans A clue for IR • 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 1.Krawczyk M. Pol Arch Med Wewn. Mar 2009;119(3):180-3. 2. Sadeghian G. J Dermatol. Apr 2009;36(4):209-12 Problem Lists • Obesity • Acanthosis nigricans • Lipodystrophy (mild facial lipoatrophy) • FBS = 159mg/dl (Provisional DM) • Metabolic syndrome? Lipodystrophy in HIV-infected children 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 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 Characteristics of Lipodystrophy from Protease Inhibitors • Fat gain on abdomen, breast, and dorsocervical hump • Fat loss from peripheral extremities • Fat gain in visceral organs 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 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% Alam NM. J Acquir Immune Defic Syndr. 2012 March 1; 59(3): 314–324 Thailand, N=202, LD = 25% Receiving PI 41%, Received d4T 60% Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501 Facial lipoatrophy Is it reversible? Facial Lipoatrophy may improve after stopping d4T 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 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 Interpretation of Fasting Blood Sugar Normal FBS Provisional DM Impaired FBS FBS 100 mg/dl 126 mg/dl 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 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 Diagnosis of Diabetes Mellitus 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% 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 9 yo. boy with acanthosis nigricans Oral Glucose Tolerance Test 0 30 60 90 120 BS 58 134 181 165 188 Insulin 88.7 842.3 >1000 >1000 >1000 Diagnosis: Impaired OGTT with hyperinsulinemia>>Pre-diabetes Normal fasting lipid profile Chol LDL-C HDL-C TG 174 120 51 140 Insulin Resistance and Type 2 Diabetes in HIV-Infected Children 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 1.Vigouroux C. Diabetes & Metabolism 1999 2. Bitnun A. J Clin Endocrinol Metab 2005 Insulin Resistance and HIV Classical T2DM risk HIV-associated risk factors factors Peripheral lipoatrophy Obesity (abdominal) Physical inactivity Increased liver or muscle fat Genetic Inflammatory cytokines Family history Race Older age Dyslipidemia Low testosterone Oxidant stress HCV infection PIs therapy How can we prevent DM in this patient? A. Diet and exercise B. Diet and exercise and metformin C. Control other factor: dyslipidemia Exercise and Metformin can prevent DM Reduction in the Incidence of T2 DM with Lifestyle Intervention or Metformin • 3234 patients with IFG or IGT • Treatment; placebo, metformin, lifestylemodification program • Lifestyle-modification program: 7% weight loss and 150 mins of physical activity per week • Average follow-up was 2.8 yr Diabetes Prevention Program. N Engl J Med 2002:346:393-403 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% Diabetes Prevention Program. N Engl J Med 2002:346:393-403 Drugs that may delay or prevent the development of Type2 DM 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 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) After 4 months of Metformin Rx and exercise: Improved hyperinsulinemia and BS OGTT 8/11/06 0 30 60 90 120 58 88.7 134 842.3 181 >1000 165 >1000 188 >1000 0 30 60 90 120 58 13.19 95 130.9 116 249.4 99 139.3 99 161.1 BS Insulin OGTT 12/1/07 BS Insulin 6 Months later…He developed hyperlipidemia Fasting lipid profile Date Chol LDL-C HDL-C TG 7/25/06 12/7/07 174 232 120 138.4 140 113 51 71 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. 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! 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 1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004. 3. Amaya RA. Pediatr Infect Dis J. 2002 Metabolic complications: >>Start from lipodystrophy, >>dyslipidemia, insulin resistance End up with cardiovascular diseases, stroke, DM Dyslipidemia found 40%-80% in children, associated with receiving PI and lipodystrophy1-3 Prevalence of Dyslipidemia in a European cohort of HIV-infected children and adolescents (N=426), 60% receiving PI4 Fasting Hypertriglyceridemia 66% 45% 21% Hyper-cholesterolemia 49% 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 Defic Syndr. 2012 March 1; 59(3): 314–324 Frequency of abnormal lipid profile in Thai adolescents Siriraj, Bangkok, 2013 HIV-infected Healthy N = 100 Total = 50 P value CHOL > 200 mg/dl LDL > 130 mg/dl 25 (25%) 12 (24%) 0.867 16 (16%) 8 (16%) 0.733 HDL < 35 mg/dl 8 (8%) 0 (0) 0.017 TG > 150 mg/dl 37 (37%) 49% receiving PI 1 (2%) <0.001 V. Poomlek. 7th IAS 2013, KL, MOPE047 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. What else can we do other than even more encouraging lifestyle modification? A: Change ARV B: Start statin C. Start fibrate Treatment of dyslipidemia in children • 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 Intervention in this patient: • Educate for life style modification: Low fat diet and exercise • Change LPV/r to ATV/r Lipid Changes at Week 48 with Baseline in PI Studies He started to be uneasy to take ARV Date %CD4 CD4 count VL Medication 1/6/2010 (12 Y) 20.58 572 - AZT+3TC+ATV/ r 7/9/2010 (12 Y) - - - TDF+3TC+ATV/ r 18/3/2011 (13 Y) 22.88 510 **Once daily regimen <40 TDF+3TC+ATV/ r Fasting Blood Sugar : 138mg/dl Cholesterol 155 mg/dl Triglyceride 159 mg/dl LDL 74 mg/dl HDL 50 mg/dl Diet education for dyslipidemia High Cholesterol Diet High Triglyceride Diet Diabetic diet education 5 Years after starting treatment And became a teenager 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 Follow-up • FBS • HbA1C 400 mg/dl Dx: DM Start Insulin SC 13.8 % Does he meet the criteria for metabolic syndrome? …..Yes or No 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 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 International Diabetes Federation (IDF) Criteria for MS in Children Age group Obesity (WC) TG (mg/dl) HDL-C (mg/dl) BP (mmHg) BG (mg/dl) 6<10 ≥90th% tile 10<16 ≥90th% tile or adult cut-off ≥150 <40 Sys≥130 or Dias≥85 FBG ≥100 or T2DM ≥16 ≥90 cm in male, ≥80 cm in female ≥150 <40 in male, <50 in female Sys≥130 or Dias≥85 FBG ≥100 or T2DM 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 Criteria Dx Metabolic syndrome in this patient BW > P97 Triglyceride > 150 mg/dl FBS > 100 mg/dl BP 120/80-128/80 mmHg HDL 45-50 mg/dl Metabolic syndrome among HIV-infected patients: related factors Incidence 5.1% in <30 yo., 27% in 50-59 yo. Jerico C. Diabetes Care. 2005 Jan;28(1):132-7. Pathogenesis of Metabolic Complications in HIV-infected Patients HIV infection increase inflammatory cytokines TNF inhibits the uptake of FFA by adipocyte, increase lipogenesis IL-6 and adipocytokines cause dyslipidemia and lipodystrophy May directly induce insulin resistance Protease inhibitor Effect several steps causing dyslipidemia, IR, and lipodystrophy NRTI Cause mitochondrial dysfunctionlactic acidosis adipocyte death Development of HIV and PI associated lipodystrophy/ IR 11β-HSD1, 11βhydroxysteroid dehydrogenase type 1; FFA, free fatty acids; ROS, reactive oxygen species; Anuurad E. Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):478-85. Screening and intervention for metabolic complications in HIV-Infected Patients is needed especially for patients at risk Contribution of risks factors for CAD in HIV-Positive Persons 1.04 1.25 1.47 Estimated effect (95%CI) on the odds ratio of a first CAD event for: - genetic risk score quartile (black dots), - HIV-related variables (gray triangles) - traditional CAD risk factors (gray squares). Rotger M. CID 2013 Jul;57(1):112-21. Physical exam/wt/ht/wc Check FBS, Lipid q 6 mo. Impaired FBS Oral Glucose Tolerance Test (OGTT) Dyslipidemia • Glucose 1.75g/kg/dose (Max 75g) • Blood for Blood sugar and insulin • (at 0, 60, 120 min) • Life style modification • ART modification • Lipid lowering agent if not response Impaired OGTT Hyperinsuline mia • Start Metformin • DM education • Life style modification • ART modification normal •F/U FBS q 3-6 months F/U FBS, HbA1C q 3 months if • HbA1C > 9 or • FBS > 200 mg/dl Start Insulin SC Management of Metabolic Complications in HIV-Infected Children and Adolescents • Step 1 • Lifestyle modification with diet and exercise • Weight control • Change PI to NNRTI or ATV/r or DRV/r, may consider unboosted ATV or low dose LPV/r • Step 2 • Metformin (for >10 yo) if impair OGTT, or Insulin injection if meet criteria for DM • Fibrate if TG>400 mg/dl • Lowest dose statin (pravastatin or atorvastatin) if TC > 200 mg/dl (approve in > 8 yo) Need to work with the family and psychological support Therapeutic Goals Glycemic recommendations HbA1c <7% FBG: 70-130 mg/dL Fed glucose <180 mg/dl Weight/diet BMI < 25 kg/m2 Exercise > 150 min/week Diet <7% saturated fat Adapted from ADA and EASD consensus 2009 Therapeutic Goals Dyslipidemia • LDL-C < 100 mg/dl • HDL-C > 35 mg/dl • TG < 150 mg/dl Blood pressure • Established HT in children: BP < 95th % for age, sex and height Adapted from ADA and EASD consensus 2009, Libman IM. 2007 How to treat LD? • Stop using d4T (do not use d4T for > 6 months) >> Phasing out d4T • Avoid PI (may not be possible, or use ATV/r or DRV/r • Medical: None is really effective and practical • Liposuction for severe buffalo hump • Filling therapy for facial lipoatrophy: may consider in adults Before After Prevention of Metabolic Complications in HIV-Infected Children & Adolescents Healthy life style weight control regular exercise low saturated fat diet, eat fish and veggies No smoking Avoid PI (25% of Asian children are receiving PI) Serious with adherence to first line NNRTI regimens, NVP has the least long-term problem Screening and early intervention in borderline dyslipidemia Cardiac dysfunction Cardiomyopathy associated with severe HIV diseases and improved with HAART. However, long term ART may associated with increased cIMT. 3 year- old girl with pneumonia and cardiomyopathy • Echocardiogram before ART (14/6/2010) – Severe MR – LV dilatation with hypokinesia LV wall, LVEF 16% – Minimal pericardial effusion – Imp: Dilated cardiomyopathy with severe MR • CD4= 1,346 (14%), VL 1.5x106 • Treatment – ATB, Lasix, aldactone, dobutamine – Start AZT/3TC/NVP • At 10 yo still have abnormal LVEF How can we prevent early CHD in HIV-infected children receiving ART? A. Start ART early B. Strengthen adherence to NNRTI regimen C. Diet and excercise Structural and Functional Vasculature Changes in HIV-Infected Children • Carotid intima-media thickness (IMT): • Increased in HIV-infected vs control uninfected children (p<0.001). • In infected children, PI treatment associated with increased carotid IMT. • HIV+ control * p=0.04 **p=0.01 • Suggests both HIV & antiretroviral drugs play role. Charakida M et al. Circulation 2005;112:103-9 Untreated Non-PI treated PI treated The cIMT in association with on PI > 6 months in HIV-infected Thai adolescents cIMT (mm) Receiving PI > 6 Receiving PI < 6 months (n=53) months or P value never(n=47) Proximal CCA 0.393 (0.284-0.478) 0.369 (0.289-0.448) 0.019 Distal CCA 0.40 (0.273-0.475) 0.381 (0.311-0.441) 0.022 ICA 0.353 (0.283-0.514) 0.345 (0.26-0.431) 0.179 Overall cIMT 0.379 (0.284-0.451) 0.372 (0.287-0.423) 0.02 The values were presented in median (range) Low bone mass, Osteopenia and Vitamin D deficiency A 15 years old Thai boy with growth failure Age Regimen CD4 VL 7y AZT+3TC+EFV 45 >75,0000 8y “ 461 26,400 11 y AZT+3TC+TDF+LPV/r 12 y “ 638 163 13 y “ 784 < 40 • At 1 year-old, he had recurrent severe pneumonia, delayed development, and growth failure. • At 5 year-old, he had pulmonary TB • He always be very small despite successful antiretroviral therapy DXA scan of lumbar spine (L2-L4) Bone densitometry (Dual-energy x-ray absorptiometry; DXA) performed at 15 year-old BMD Z-score Adjust to height age (12 y) 0.721 -0.9 Adjust to Thai reference (15 y) 0.721 -2.1 Both HIV and ARV Associated with Osteopenia: A meta-analysis Brown TT. AIDS 2010;20:2165-74. Bone Mass Accumulate From Childhood and Loss in Adulthood Greatest bone mass gain at spine and hip is at: - Girls: 11-14 yo. Tanner 2-4 - Boys: 13-17 yo. Tanner 4 Therefore, prevention of osteoporosis and fracture must be started in childhood Theintz G. J Clin Endocrinol Metab 1992;75:1060-5. Rizzoli R. Osteoporos Int 1999;9 (suppl 2):S17-23. Bone mineral content is lower in prepubertal HIV-infected children Healthy HIV+ Age versus total body bone mineral content (TBBMC) adjusted for sex, race, height, and weight in HIV-infected (squares) and healthy (diamonds) prepubertal children. Arpadi SM. JAIDS 2002;29:450-4. Prevalence of low BMD measured by spine BMD (L2-L4) in Thai HIV-infected adolescents: The first study in Asia Adjusted for Thai reference % N=98 Z-score percentage % % % BMD Puthanakit P. J Acquir Immune Defic Syndr. 2012 Aug 22 Pathogenesis of osteoporosis in HIV-infected patients Protease inhibitors HIV (gp120) Other cells CD4 T cells TDF associated PRTD HIV (Tat) RANKL M-CSF Osteoclast differentiation RANKL, OPG Receptor activator of nuclear factor kappa-B ligand Osteoprotegerin ligand Osteoclast activity Bone resorption - Low calcium intake - Vit D deficiency Osteopenia Osteoporosis Increased bone turnover Vitamin D and clinical disease progression in HIV infection: EuroSIDA study Kaplan–Meier estimation of progression. Kaplan–Meier estimation of progression to (a) AIDS-defining events, (b) all-cause mortality, and (c) non-AIDS-defining events according to 25(OH)D concentration tertile at baseline. Viard JP. AIDS 2011:25:1305-15. Association of Vitamin D Insufficiency with Carotid Intima-Media Thickness in HIV-Infected Persons Adjusted Mean Carotid IntimaMedia Thickness by Vitamin D Category*After adjustment for traditional cardiovascular risk factors and HIV-related factors, a graded relationship between vitamin D levels and carotid IMT was observed, P 5 .021). *Carotid intima-media thickness predicted by the multivariable linear regression model after adjustment for age, sex, race, coronary heart disease, hypertension, dyslipidemia, pack-years of smoking, NRTI duration, HIV duration, season, total cholesterol, LDL, waist to hip ratio, and calcium supplementation, corrected calcium, alkaline phosphatase, parathyroid hormone, and 1,25OH vitamin D level. Error bars represent 95% confidence intervals. Choi AI. CID 2011;0:1-4. Association between initiation of antiretroviral therapy with efavirenz and decreases in 25-hydroxyvitamin D • EFV induces CYP3A4 and CYP24, reducing CYP2R1, the enzyme involving in Vit D metabolism Brown TT. Antiviral Therapy 2010;15:425-9. Prevalence of vitamin D deficiency in Thai HIV-infected adolescents: As High as Healthy Thai Children In healthy children 19% were <20 ng/ml, and 60% were 20-30 ng/ml Reesukumal K. Clinical Chemistry 2012;58(10) Supplement:A153. % Vitamin D category In HIV-infected adolescents 46% 29% 25% Deficiency Insufficiency Chokephaibulkit K. PIDJ 2013 Kidney Dysfunction Screening is important because early renal diseases are asymptomatic Incidence of Persistent Renal Dysfunction in HIV-Infected Children in PACTG 219/219c Incidence of new renal lab abnormalities was 3.7 events/100 child-years, with rates increasing between 1993-2005 Andiman W et al. Pediatr Infect Dis J 2009;28:619-25 Estimated chronic kidney disease and antiretroviral drug use in HIV-positive patients CKD defined as confirmed (persisting for 3 months) decrease in eGFR to 60 ml/min per 1.73m2 or less if eGFR at baseline above 60 ml/min per 1.73m2 or confirmed 25% decrease in eGFR if baseline eGFR 60 ml/min per 1.73m2 or less). Mocroft A. AIDS 2010;24:1667-78. No chance for HIV-infected children with renal failure 13 year-old girl died from CRF An episode of HSV stomatitis • At 5 yo, presented with nephrotic syndrome responded well to HAART and steroid • She has been virologic suppressed with normalized CD4 for more than 6 years • At 12 yo, presented with renal failure required renal replacement with CAPD • Experienced several peritonitis events and failed CAPD • She was refused for hemodialysis and renal transplantation Neuro-psychiatric issues Impact of HAART on HIV encephalopathy among perinatally infected children and adolescents. Incidence of HIV encephalopathy and percentage of Patel AIDS 2009;23:1893-1901. children on HAART from 1994 to K. 2006. Mental Health Disorders in HIV-Infected Children and Adolescents • Review of 8 studies including 328 HIV-infected children age 4-21 years; prevalence compare with overall population percent 35 29% 30 25 25 % 24% 20 15 10 5 0 ADHD Increased risk ratio 6x Anxiety Dis 3.8x Depression 7.1x Scharko AM. AIDS Care 2006;18:441-5 Impact of HIV Severity on Cognitive and Adaptive Functioning During Childhood and Adolescence % impairment Exposed uninfected Infected w/o stage C Infected w stage C Smith R. PIDJ 2012;31:592-8. A 13 Year-old Girl who suddenly became furious and angry with everything Date Age Regimen CD4 VL no % 11/3/2003 8 yrs. 11 mo. Start AZT+3TC+EFV 25 0.9 40,400 10/2/2004 9 yrs. 10 mo. “ 596 19 <400 8/1/2008 13 yrs. 9 mo. “ 1,052 42 <40 Remark Wt. 35 kg. on EFV 400mg/d EFV Level=13,945 ng/ml EFV reduced to 200 mg/ day EFV Level=5,002 ng/ml Symptoms improved after dose reduction 16/6/2009 15 yrs. 2 mo. “ 912 35 <40 5/1/2010 16 yrs. 9 mo. “ 1,171 44 <40 High levels of NVP and EFV may be found in 10% of Thai children Nevirapine plasma exposure and CYP2B6 516 G>T polymorphisms after administration of GPO-VIR Z30 in HIV-infected Thai children Rate 45% 45% 10% Chokephaibulkit K. Antivir Ther 2011;16:1287-95 Without good screening and early intervention, it may end up with premature age-related comorbidities Premature Age-Related Comorbidities Among HIV-Infected Persons Compared With General Population Comparative risk of hypertension, diabetes mellitus, renal failure, cardiovascular disease, and fracture, by age, among patients versus control subjects. Guaraldi G. CID 2011;53:1120-6. Prevention of long term treatment complications • Start ARV early, prefer NNRTI for 1st regimen • Support adherence to the 1st line NNRTI regimens as long as possible>> delayed PI use • Avoid long-term d4T • Use TDF only when no other alternative NRTI • Healthy life style • Regular exercise, control weight • Get enough sun light or vit D supplement • Eat healthy, low saturated fat diet, eat fish and veggies • Get enough calcium • No addiction to drugs, games, tobacco, alcohol, etc • Screen and early treat for metabolic complications, kidney (esp. TDF), liver, neuropsychiatric, and bone health (esp. TDF) Most children and adolescents do not get enough calcium! Greer FR. Pediatrics 2011;117:578-85. Which children should be monitored BMD? • May be before or during treatment regimens with TDF or PI, especially with risks: - Lean, small, or growth failure - Have history of fracture with minimal trauma But make sure to know how to interpret. Best is to use ethnic specific reference. The different machine do not give same results, may need conversion GE-Lunar = 1.195 x Hologic – 0.023 (Fan B, et al. Osteoporos Int (2010) 21:1227–1236.) Thank you for your attention.