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
Children (<15 years) living with HIV/AIDS as of end 2007 North America 10 000 Caribbean 20 000 Latin America 45 000 Western Europe 5 000 North Africa & Middle East 40 000 sub-saharan Africa 2.2 million Eastern Europe & Central Asia 16 000 East Asia & Pacific South 4 000 & South-East Asia 240 000 Australia & New Zealand < 200 Total: 2.5 million UNAIDS
Deaths in children (<15 years) from HIV/AIDS during 2007 North America < 1000 Caribbean 1 500 Western Europe < 1000 North Africa & Middle East 4 200 sub-saharan Latin America Africa 4 900 340 000 Eastern Europe & Central Asia 1 900 East Asia & Pacific South 1 300 & South-East Asia 17 000 Australia & New Zealand < 500 Total: 380,000 UNAIDS
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 * *
1994 Revised CDC Pediatric HIV Classification: Age-Specific Immunologic Categories
HIV Pediatric Clinical Clasification Category A: Mildly Symptomatic Lymphadenopathy Hepatomegaly Splenomegaly Dermatitis Parotitis Recurrent or Persistent upper respitaory inferctions (sinusitis, otitis media)
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
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
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
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
Most Commonly o Reported ed AIDS Defining Conditions in Children Disease Number % Pneumocystis jirovecii Pneumonia 345 34 Lymphoid Interstitial Pneumonitis 283 28 Recurrent Bacterial Infections 246 24 HIV Wasting Syndrome 165 16 Candida Esophagitis 132 13 HIV Encephalopathy p 116 11 Cytomegalovirus Disease 77 7 Pulmonary Candidiasis 51 5 Cryptosporidiosis 31 3 Herpes Simplex Disease 30 3 Mycobacterium Avium Infection 29 3 CDC
Opportunistic Infections at HIV diagnosis i US: 1988-1998 1998 Dankner W. Pediatr Infect Dis J 2001;20:40-8
Opportunistic Infections in HIV- infected Children enrolled in PACTG, US: 1988-19981998 Dankner W. Pediatr Infect Dis J 2001;20:40-8
Bacterial Infections in HIV- infected Children enrolled in PACTG: 1988-19981998 Dankner W. Pediatr Infect Dis J 2001;20:40-8
Mortality Association of baseline HIV RNA and CD4 % with Mortality in Children 100 80 60 CD4 % > 15% < 15% 40 20 0 > 100,000 < 100,000 > 15% < 15% Mofenson L. JID 1997;175:1029-38
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;362:1605-11
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;362:1605-11
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
Principles of Management Early Diagnosis Prophylaxis against opportunistic infections Monitor immune status Monitor virologic status Immunizations: Influenza, Pneumococcal Antiretroviral therapy
Principles of Management Monitor medication adherence Evaluate side effects from medications Nutritional support Monitor growth and development Environmental and social support Acute medical care
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 15-25 % Any Value or >100,000 Copies/mL Treat Consider Treatment and and Monitor > 25 % < 100,000 Closely Copies/mL
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
ad s /m L) iral Lo copies V i (log c LM; 26 mo F, Perinatal HIV 100000 7000 10000 1000 100 10 1 d4t, 3TC, Ritonavir i 0 2 8 14 20 26 months 6000 5000 4000 3000 2000 1000 0 e ll u L) D4 T ce unt (/u C D co
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
Increase in Z-scores in HIV infected Children with Virologic Response Guillen S. Pediatr Infect Dis J 2007;26:334-8
HIV Life Cycle
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
Antiretroviral Agents Non-Nucleoside Nucleoside Reverse Transcriptase Inhibitors: Nevirapine (NVP) Viramune Efavirenz (EFV) Sustiva Delavirdine (DLV) Rescriptor TMC 125 Etravirine TMC 278
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
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
HIV Entry Inhibitors Moore, JP. (2003) PNAS. USA 100:10598
When to Change HAART Regimen in Chidren Virologic Failure Immunologic Failure Clinical Failure Availability of new drugs
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
Proportion of Children with Undetectable Viral Load: P1021 McKinney R et al. Pediatrics 2007;120:e416-e423
Changes in CD4 Count from Baseline: P1021 McKinney R. et al. Pediatrics 2007;120:e416-e423
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% 60 50 PK target based AUC 30 40 µg/h/ml 30 Accepted dose (RTV 20 boosted): 24 weeks VL< 400 20 P<001 0.01 3 m to 13 y powder: 310 10 mg/m2 0 2 y to 21 y capsule: 210 Naïve Exper mg/m2 Rutstein R. et al CROI 2008 Abstract 715
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.
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.
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.
SL 5 Year F, Perinatal HIV vira l Lo ad (lo g cop ie s/m L ) 1,000,000 10,000000 100 1 0 1 4 9 14 21 D4t 3TC NFV months 1500 1000 500 0 c ell ul) 4 T c u nt (/ CD cou
Case History (SL) Albumin g/dl 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 Baseline 1 month 4 month 14 month
Case History (SL) Protein/creatinine ratio* 50 45 40 35 30 25 20 15 10 5 0 Baseline 1 month 4 month 14 month * Normal: < 0.2
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.
Generalized BCG infection Presented at 7 months with axilar adenitis Treated INH RFP and PZA were added HIV + CD4 72 cells/µl VL > 750,000 000 cpm d4t-3tc-efv Cipro-ETB
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
HAART Toxicity Laboratory: Anemia, neutropenia Increase bilirubin, SGOT, SGPT Increase CPK Increase Amylase Lactic acidosis Hypertrigliceridemia, Hyperglycemia Increase creatinine, tubular acidosis Renal stones
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
Changes in T-cells and VL in Children who discontinued HAART A. CD4 + and CD8 + T cells percentages B. Plasma HIV-1 RNA (%) Percentage 20 30 40 50 60 10 CD8+ T cells CD4+ T cells N=72 61 59 45 34 24 13 RNA (cp/ml) Log1 10 plasma HIV-1 5 5.0 5.5 3.5 4.0 4. 3.0 N=72 61 59 45 34 24 13 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Month of Treatment Interruption Month of Treatment Interruption Saitoh A. Pediatrics 2008;121:e513-e521
Two Cases Experienced Opportunistic Infections (N=16) Age at TI (years old) 17.8 Case 1 Case 12 17.8 90 9.0 Duration of Observation (days) 412 223 Nadir CD4 Percents (%) 4 24 Initial CD4 Counts (/µl) 43 1219 Initial CD4 Percents (%) 4 28 Initial Plasma HIV-1 RNA (copies/ml) 5.17 5.17 CD4 Counts when OI (/µl) (/µ L) 5 459 CD4 Percents when OI (%) 1 26 Plasma HIV-1 RNA when OI 5.57 (copies/ml) OI 5.57 5.43 Disseminated MAC infection Miliary tuberculosis
Survival Distribution Function: TB related Mortality in HIV positive and HIV negative children in Addis Ababa, Ethiopia % Surviving 100 HIV - 80 60 HIV + 40 20 0 5 10 15 20 25 Time to death (months) Pediatr Infect Dis J 2002;21:1053-61
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
Progression to AIDS in Infants with Vertically acquired HIV in Durban, South Africa % AIDS Free 100 80 60 40 20 0 2 6 12 18 24 Time to death (months) Ann Trop Paed 1998;18:187-96
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
HIV & Severe Pulmonary Disease 11 year old girl Dx TB in 2002. 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.
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
Hospitalizations among HIV infected children; Southern California i 1994-2001 35 30 25 20 15 10 5 0 p<0.0001 1994 1995 1996 1997 1998 1999 2000 2001 Year No. of children hospitalized % of children hospitalized Viani, R. et al. CID 2004;39:725-31
Mean CD4% and viral load; Southern California 1994-2001 35 p=0.0067 5 30 4.5 4 25 3.5 CD4% 20 15 p<0.001 3 2.5 2 log VL 10 1.5 1 5 0.5 0 1994 1995 1996 1997 1998 1999 2000 2001 0 Year Mean CD4% Mean log10 plasma HIV RNA Viani, R. et al. CID 2004;39:725-31
Hospital admission, mortality and HAART; Southern California 1994-2001 % 100 p<0.001 90 80 70 60 50 40 30 20 10 0 1994 1995 1996 1997 1998 1999 2000 2001 %Hospitalized %Deceased HAART Viani, R. et al. CID 2004;39:725-31
Hospital Admission, Mortality and HAART use among HIV infected Children in Tijuana, Baja California, Mexico % 90 P=0.005 80 70 60 50 40 30 20 10 0 1998 1999 2000 2001 2002 2003 2004 2005 P= 0.15 P=0.03 %Hospitalized %Deceased HAART Viani, RM CROI 2007
Causes of Death among HIV infected Children in Tijuana, Baja California, Mexico: 1998-2005 Sepsis, 1 CMV, 1 Meningitis, iti 2 PCP, 3 Pneumonia, 9 TB, 3 Viani, RM CROI 2007
Median Survival: birth to death or last follow up among HIV infected children in San Diego (1994-2001) )& Tijuana (1998-2005) %S Surviving ii 100 80 60 San Diego* Tijuana 40 20 0 24 48 72 96 120 144 168 192 Time to death (months) *Viani et al CID 2004