Total: 2.5. million East Asia & Pacific UNAIDS. Eastern Europe & Central Asia. Western Europe. North America. North Africa & Middle East

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1 VIH Pediatrico: Diagnostico & Manejo Rolando M. Viani, i MD, MTP, FAAP Profesor Asociado de Pediatría División de Infectología Pediátrica Escuela de Medicina de la Universidad de California San Diego

2 Children (<15 years) living with HIV/AIDS as of end 2007 North America Caribbean Latin America Western Europe North Africa & Middle East sub-saharan Africa 2.2 million Eastern Europe & Central Asia East Asia & Pacific South & South-East Asia Australia & New Zealand < 200 Total: 2.5 million UNAIDS

3 Deaths in children (<15 years) from HIV/AIDS during 2007 North America < 1000 Caribbean Western Europe < 1000 North Africa & Middle East sub-saharan Latin America Africa Eastern Europe & Central Asia East Asia & Pacific South & South-East Asia Australia & New Zealand < 500 Total: 380,000 UNAIDS

4 Clinical and laboratory monitoring of the HIV- exposed Infant 0wk 2wk 4-6wk 4m 18m Clinical Assessment PACTG 076 HIV DNA PCR T-cells * * * * * * * * * * * * HIV ab * PCP Prophylaxis * *

5 1994 Revised CDC Pediatric HIV Classification: Age-Specific Immunologic Categories

6 HIV Pediatric Clinical Clasification Category A: Mildly Symptomatic Lymphadenopathy Hepatomegaly Splenomegaly Dermatitis Parotitis Recurrent or Persistent upper respitaory inferctions (sinusitis, otitis media)

7 HIV Pediatric Clinical Clasification Category B: Moderately Symptomatic Anemia (<8 gm/dl), Neutropenia (< 1,000/mm3) or Thrombocytopenia (< 100K) Bacterial meningitis, pneumonia, sepsis Oropharyngeal candidiasis > 6 m old Cardiomyopathy, hepatitis, nephropaty CMV, Toxoplamosis, HSV pneumonitis or esophagitis with onset < 1 month

8 HIV Pediatric Clinical Clasification Category B: Moderately Symptomatic Chronic Diarrhea Fever lasting > 1 month Recurrent HSV stomatitis Complicated varicella, recurrent Zoster or involving more than one dermatome Leiomyosarcoma, Nocardiosis LIP

9 HIV Pediatric Clinical Clasification Category C: Severely Symptomatic Recurrent serious bacterial infections Wasting syndrome: > 10% weight loss or downward crossing of 2 percentile lines or < 5th % of Wt for Ht Plus chronic diarrhea/fever Encephalopathy: developmental delay or microcephaly or brain atrophy in < 2 y or acquired symmetric motor deficits it

10 HIV Pediatric Clinical Clasification Category C: Severely Symptomatic Esophageal candidiasis Disseminated coccidioidomycosis, histoplasmosis, MAC, TBC, extrapulmonary cryptococcosis cryptosporidiosis, isosporiasis CMV retinitis, colitis or CNS, cerebral toxoplasmosis Mucocutaneous HSV, PCP, KS, PML, recurrent Salmonella

12 Most Commonly o Reported ed AIDS Defining Conditions in Children Disease Number % Pneumocystis jirovecii Pneumonia Lymphoid Interstitial Pneumonitis Recurrent Bacterial Infections HIV Wasting Syndrome Candida Esophagitis HIV Encephalopathy p Cytomegalovirus Disease 77 7 Pulmonary Candidiasis 51 5 Cryptosporidiosis 31 3 Herpes Simplex Disease 30 3 Mycobacterium Avium Infection 29 3 CDC

13 Opportunistic Infections at HIV diagnosis i US: Dankner W. Pediatr Infect Dis J 2001;20:40-8

14 Opportunistic Infections in HIV- infected Children enrolled in PACTG, US: Dankner W. Pediatr Infect Dis J 2001;20:40-8

15 Bacterial Infections in HIV- infected Children enrolled in PACTG: Dankner W. Pediatr Infect Dis J 2001;20:40-8

16 Mortality Association of baseline HIV RNA and CD4 % with Mortality in Children CD4 % > 15% < 15% > 100,000 < 100,000 > 15% < 15% Mofenson L. JID 1997;175:

17 Likelihood of Developing AIDS Within 12 Months By Age & CD4 % in Children on No Therapy or ZDV % With AIDS 64.9% 56.2% 51.4% 45.6% 70% 60% 50% 40% 30% 20% 10% 0% 40.5% 30.8% 40.0% 28.6% 20.5% 28.8% 31.2% 14.7% 18.0% 7.4% 24.9% 20.9% 7.6% 5% 12.0% 3.4% 15.9% 10% 20.5% 4.7% 8.8% 2.2% 15% 12.8% 3.6% 1.9% 20% 7.2% 3.1% 25% 1.8% 30% CD4 % 6 mos 1 yr 2 yr 5 yrs 10 yrs Age Lancet 2003;362:

18 Likelihood of Death Within 12 Months By Age & CD4 % in Children on No Therapy or ZDV % Mortality 50.6% 38.3% 3% 60% 50% 40% 30% 20% 10% 0% 25.9% 28.7% 19.5% 13.0% 11.7% 6.9% 17.0% 10.7% 5.0% 2.3% 5% 11.0% 5.9% 2.2% 10% 1.0% 6.5% 10% 3.4% 7.9% 1.2% 0.5% 15% 4.5% 2.2% 20% 0.7% 6.2% 0.3% 3.4% 25% 1.6% 0.5% 0.2% 30% 6 mos 1 yr 2 yrs 5 yrs 10 yrs CD4 % Age Lancet 2003;362:

19 Are HIV-infected children different? Disease progression is more rapid CNS disease and growth failure common HIV RNA load and CD4 count higher Different pharmacokinetics Adherence depends on caregivers Greater potential for immune reconstitution

20 Principles of Management Early Diagnosis Prophylaxis against opportunistic infections Monitor immune status Monitor virologic status Immunizations: Influenza, Pneumococcal Antiretroviral therapy

21 Principles of Management Monitor medication adherence Evaluate side effects from medications Nutritional support Monitor growth and development Environmental and social support Acute medical care

22 Indications for Initiation of ART in Children > 1 Year Clinical CD4 Cell % Category Plasma HIV Recommend RNA cpm AIDS or Clinical Category C Clinical Category B Asymptomatic or < 15 % or % Any Value or >100,000 Copies/mL Treat Consider Treatment and and Monitor > 25 % < 100,000 Closely Copies/mL

23 Aims of Antiretroviral Treatment Provide combination therapy Immune reconstitution Decrease viral load to undetectable levels Clinical improvement: Weight gain Normal development Improved quality of life

24 ad s /m L) iral Lo copies V i (log c LM; 26 mo F, Perinatal HIV d4t, 3TC, Ritonavir i months e ll u L) D4 T ce unt (/u C D co

25 HAART Impacts on Weight and Height in HIV-infected Children Children starting HAART after 1997 in Madrid, Spain Weight, height and BMI converted to Z- score Changes in Z-score Wt, Ht and BMI from baseline- 60 months 264 HIV-infected children, median age at initiating HAART 6 y. HAART naïve: 39% Virologic response 51% Guillen S. Pediatr Infect Dis J 2007;26:334-8

26 Increase in Z-scores in HIV infected Children with Virologic Response Guillen S. Pediatr Infect Dis J 2007;26:334-8

27 HIV Life Cycle

28 Antiretroviral Agents Reverse Transcriptase Inhibitors (NARTI): Zidovudine (ZDV) Retrovir Lamivudine (3TC) Epivir Didanosine (ddi) Videx Zalcitabine (ddc) HIVID Stavudine (d4t) Zerit Abacavir (ABC) Ziagen Tenofovir (TDF) Viread

29 Antiretroviral Agents Non-Nucleoside Nucleoside Reverse Transcriptase Inhibitors: Nevirapine (NVP) Viramune Efavirenz (EFV) Sustiva Delavirdine (DLV) Rescriptor TMC 125 Etravirine TMC 278

30 Antiretroviral Agents Protease Inhibitors: Saquinavir (SQV) Fortavase, Invirase Ritonavir (RTV) Norvir Indinavir (IDV) Crixivan Nelfinavir (NFV) Viracept Amprenavir (APV) Agenerase Lopinavir/r (LPV/r) Kaletra Atazanavir (ATV) Reyataz Fosamprenavir (LXV) Lexiva Tipranavir TMC 114 Darunavir

31 New Antiretroviral Targets Entry Inhibitors: Fusion Inhibitor: Enfuvirtide (T-20) Fuzeon, Co-receptor Inhibitors: Maraviroc, Vicriviroc Attachment Inhibitors: PRO542, BMS806 Integrase Inhibitors: MK-0518 Raltegravir GS-9137 Alvitegravir

32 HIV Entry Inhibitors Moore, JP. (2003) PNAS. USA 100:10598

33 When to Change HAART Regimen in Chidren Virologic Failure Immunologic Failure Clinical Failure Availability of new drugs

34 Long-term Safety and Efficacy of a Once-Daily Regimen of Emtricitabine, i Didanosine, i and Efavirenz in HIV-Infected, Infected, Therapy-Naive Children and Adolescents: PACTG P1021 McKinney R et al. Pediatrics 2007;120:e416-e423

35 Proportion of Children with Undetectable Viral Load: P1021 McKinney R et al. Pediatrics 2007;120:e416-e423

36 Changes in CD4 Count from Baseline: P1021 McKinney R. et al. Pediatrics 2007;120:e416-e423

37 Atazanavir in HIV-Infected Infected Children & Adolescents: P1020A Age: 3 m to 21 y 71% Black, 23% Hispanic 80 ART experienced: 44% 70 Toxicities: hyperbilirubinemia: 10% PK target based AUC µg/h/ml 30 Accepted dose (RTV 20 boosted): 24 weeks VL< P< m to 13 y powder: mg/m2 0 2 y to 21 y capsule: 210 Naïve Exper mg/m2 Rutstein R. et al CROI 2008 Abstract 715

38 Case History (SL) 5 1/2 year old African-American American girl presented with 2-week history of cough, chest pain, vomiting, loose stools,,p progressive abdominal distention, anorexia, asthenia and fever. PMH: recurrent oral thrush for the past 2 months and numerous episodes of AOM for the last 5 years.

39 Case History (SL) PE: Wt 15 Kg (5th) Ht 103 cm (< 5th) Chronically ill, oropharyngeal thrush, scattered rhonchi and decreased breath sounds in both lung bases. Her abdomen was distended, diffusely tender, ascites with no organomegaly. Pitting edema was noted.

40 Case History (SL) Chest x-ray: Consolidation of RUL & LLL with bilateral pleural effusion. PPD (-) Laboratory exams revealed lymphopenia and nephrotic syndrome. Blood Culture: Streptococcus pneumoniae.

41 SL 5 Year F, Perinatal HIV vira l Lo ad (lo g cop ie s/m L ) 1,000,000 10, D4t 3TC NFV months c ell ul) 4 T c u nt (/ CD cou

42 Case History (SL) Albumin g/dl Baseline 1 month 4 month 14 month

43 Case History (SL) Protein/creatinine ratio* Baseline 1 month 4 month 14 month * Normal: < 0.2

46 OC 7yMexicanboy with transfusion acquired HIV presents with cough and SOB of 2 years. A Mantoux test is 0 mm and a BAL is negative for Fungus Mycobacteria, and Bacteria.

48 Generalized BCG infection Presented at 7 months with axilar adenitis Treated INH RFP and PZA were added HIV + CD4 72 cells/µl VL > 750, cpm d4t-3tc-efv Cipro-ETB

53 HAART Toxicity Symptoms & Signs Nausea, vomiting Abdominal pain Diarrhea Rash Fatigue Renal colic Peripheral neuropathy; tingling Headache Lipodystrophy Vivid dreams, insomnia Immune Restoration Hypersensitivity reaction

54 HAART Toxicity Laboratory: Anemia, neutropenia Increase bilirubin, SGOT, SGPT Increase CPK Increase Amylase Lactic acidosis Hypertrigliceridemia, Hyperglycemia Increase creatinine, tubular acidosis Renal stones

56 Reasons for Treatment Discontinuation in HIV-infected Children Adverse effects 5 (5%) Behavior issues 9 (10%) Toxicities 10 (12%) Psychiatric diseases 2 (2%) Social issues 12 (14%) Medication fatigue 50 (57%) Saitoh A. et al. Pediatrics 2008;121:e513-e521

57 Changes in T-cells and VL in Children who discontinued HAART A. CD4 + and CD8 + T cells percentages B. Plasma HIV-1 RNA (%) Percentage CD8+ T cells CD4+ T cells N= RNA (cp/ml) Log1 10 plasma HIV N= Month of Treatment Interruption Month of Treatment Interruption Saitoh A. Pediatrics 2008;121:e513-e521

58 Two Cases Experienced Opportunistic Infections (N=16) Age at TI (years old) 17.8 Case 1 Case Duration of Observation (days) Nadir CD4 Percents (%) 4 24 Initial CD4 Counts (/µl) Initial CD4 Percents (%) 4 28 Initial Plasma HIV-1 RNA (copies/ml) CD4 Counts when OI (/µl) (/µ L) CD4 Percents when OI (%) 1 26 Plasma HIV-1 RNA when OI 5.57 (copies/ml) OI Disseminated MAC infection Miliary tuberculosis

59 Survival Distribution Function: TB related Mortality in HIV positive and HIV negative children in Addis Ababa, Ethiopia % Surviving 100 HIV HIV Time to death (months) Pediatr Infect Dis J 2002;21:

60 Natural History Of Perinatal HIV infection in South African Children 48 vertically acquired HIV and 93 HIV - infants were followed for 26 months. 70% of infected infants were symptomatic by 6 months. Relative risks for HIV infection were: Lymphadenopathy 4.5 failure to thrive 4.48 and neurologic abnormalities 3.3 The most frequent findings: Diarrhea 78%, Pneumonia 76% and Lymphadenopathy 70%. Ann Trop Paed 1998;18:187-96

61 Progression to AIDS in Infants with Vertically acquired HIV in Durban, South Africa % AIDS Free Time to death (months) Ann Trop Paed 1998;18:187-96

62 Pediatric HIV Associated Mortality in Africa: Pooled analysis 60% 52% 50% 35% 40% 30% % Mortality 20% 10% 0% 1 y 2 y Newell ML, Lancet 2004;364:1236

64 HIV & Severe Pulmonary Disease 11 year old girl Dx TB in She presented with cough and dyspnea & bilateral interstitial infiltrates. Tx for TB x 6 months no improvement. In June 2004 had pulmonary exacerbation & HIV ELISA was + Dx LIP Tx prednisone but d/c 8 weeks later.

65 HIV & Severe Pulmonary Disease September 2004 fever, cough respiratory distress & cyanosis. Clubbing & cor-pulmonale Worsening x ray Clinical TB was Dx TB Tx: RIP later STM was added Four month later: O2 dependent afebrile. Severe respiratory distress, parotid enlargement, generalized adenopathy CD4 108 cells/ul No ART given

66 Hospitalizations among HIV infected children; Southern California i p< Year No. of children hospitalized % of children hospitalized Viani, R. et al. CID 2004;39:725-31

67 Mean CD4% and viral load; Southern California p= CD4% p< log VL Year Mean CD4% Mean log10 plasma HIV RNA Viani, R. et al. CID 2004;39:725-31

68 Hospital admission, mortality and HAART; Southern California % 100 p< %Hospitalized %Deceased HAART Viani, R. et al. CID 2004;39:725-31

69 Hospital Admission, Mortality and HAART use among HIV infected Children in Tijuana, Baja California, Mexico % 90 P= P= 0.15 P=0.03 %Hospitalized %Deceased HAART Viani, RM CROI 2007

70 Causes of Death among HIV infected Children in Tijuana, Baja California, Mexico: Sepsis, 1 CMV, 1 Meningitis, iti 2 PCP, 3 Pneumonia, 9 TB, 3 Viani, RM CROI 2007

71 Median Survival: birth to death or last follow up among HIV infected children in San Diego ( ) )& Tijuana ( ) %S Surviving ii San Diego* Tijuana Time to death (months) *Viani et al CID 2004

0.14 ( 0.053%) UNAIDS 10% (94) ( ) (73-94/6 ) 8,920

0.14 ( 0.053%) UNAIDS 10% (94) ( ) (73-94/6 ) 8,920 0.14 UNAIDS 0.053% 2 250 60 10% 94 73 20 73-94/6 8,920 12 43 Public Health Service Task Force Recommendations 5-10% for Use of Antiretroviral Drugs in 10-20% Pregnant HIV-1-Infected Women for Maternal